Edward P Gelmann

Interests

Research

Prostate cancer tumor cell and molecular biologyandrogen receptorclinical trials

Teaching

Clinical OncologyMolecular Oncology

Courses

Scholarly Contributions

Journals/Publications

• Jamison, J. K., Zhou, M., Gelmann, E. P., Luk, L., Bates, S. E., Califano, A., & Fojo, T. (2024). Entinostat in patients with relapsed or refractory abdominal neuroendocrine tumors. The oncologist, 29(9), 817-e1213.
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  Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare neoplasms with an increasing annual incidence and prevalence. Many are metastatic at presentation or recur following surgical resection and require systemic therapy, for which somatostatin analogs such as octreotide or lanreotide comprise typical first-line therapies. Nonetheless, treatment options remain limited. Epigenetic processes such as histone modifications have been implicated in malignant transformation and progression. In this study, we evaluated the anti-proliferative effects of a histone deacetylase (HDAC) inhibitor, entinostat, which was computationally predicted to show anti-cancer activity, as confirmed in in vitro and in vivo models of GEP-NETs.
• Branigan, G. L., Torrandell-Haro, G., Soto, M., Gelmann, E. P., Vitali, F., Rodgers, K. E., & Brinton, R. D. (2022). Androgen-targeting therapeutics mitigate the adverse effect of GnRH agonist on the risk of neurodegenerative disease in men treated for prostate cancer. Cancer medicine, 11(13), 2687-2698.
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  Prostate cancer and multiple neurodegenerative diseases (NDD) share an age-associated pattern of onset. Therapy of prostate cancer is known to impact cognitive function. The objective of this study was to determine the impact of multiple classes of androgen-targeting therapeutics (ATT) on the risk of NDD.
• Bowen, C., Shibata, M., Zhang, H., Bergren, S. K., Shen, M. M., & Gelmann, E. P. (2020). CRISPR/Cas9-Mediated Point Mutation in Prolongs Protein Half-Life and Reverses Effects Allelic Loss. Cancer research, 80(21), 4805-4814.
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  is the most commonly deleted gene in prostate cancer and is a gatekeeper suppressor. is haploinsufficient, and pathogenic reduction in protein levels may result from genetic loss, decreased transcription, and increased protein degradation caused by inflammation or PTEN loss. NKX3.1 acts by retarding proliferation, activating antioxidants, and enhancing DNA repair. DYRK1B-mediated phosphorylation at serine 185 of NKX3.1 leads to its polyubiquitination and proteasomal degradation. Because NKX3.1 protein levels are reduced, but never entirely lost, in prostate adenocarcinoma, enhancement of NKX3.1 protein levels represents a potential therapeutic strategy. As a proof of principle, we used CRISPR/Cas9-mediated editing to engineer a point mutation in murine to code for a serine to alanine missense at amino acid 186, the target for Dyrk1b phosphorylation. , and mice were analyzed over one year to determine the levels of Nkx3.1 expression and effects of the mutant protein on the prostate. Allelic loss of caused reduced levels of Nkx3.1 protein, increased proliferation, and prostate hyperplasia and dysplasia, whereas mouse prostates had increased levels of Nkx3.1 protein, reduced prostate size, normal histology, reduced proliferation, and increased DNA end labeling. At 2 months of age, when all mice had normal prostate histology, mice demonstrated indices of metabolic activation, DNA damage response, and stress response. These data suggest that modulation of Nkx3.1 levels alone can exert long-term control over premalignant changes and susceptibility to DNA damage in the prostate. SIGNIFICANCE: These findings show that prolonging the half-life of Nkx3.1 reduces proliferation, enhances DNA end-labeling, and protects from DNA damage, ultimately blocking the proneoplastic effects of allelic loss.
• Gelmann, E. P. (2020). CRISPR/Cas9-Mediated Point Mutation in Nkx3.1 Prolongs Protein Half-Life and Reverses Effects Nkx3.1 Allelic Loss. Cancer Research, 80, 4805-4814.
• Bowen, C., Ostrowski, M. C., Leone, G., & Gelmann, E. P. (2019). Loss of PTEN Accelerates NKX3.1 Degradation to Promote Prostate Cancer Progression. Cancer research, 79(16), 4124-4134.
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  is the most commonly deleted gene in prostate cancer and a gatekeeper suppressor. NKX3.1 is a growth suppressor, mediator of apoptosis, inducer of antioxidants, and enhancer of DNA repair. PTEN is a ubiquitous tumor suppressor that is often decreased in prostate cancer during tumor progression. Steady-state turnover of NKX3.1 is mediated by DYRK1B phosphorylation at NKX3.1 serine 185 that leads to polyubiquitination and proteasomal degradation. In this study, we show PTEN is an NKX3.1 phosphatase that protects NKX3.1 from degradation. PTEN specifically opposed phosphorylation at NKX3.1(S185) and prolonged NKX3.1 half-life. PTEN and NKX3.1 interacted primarily in the nucleus as loss of PTEN nuclear localization abrogated its ability to bind to and protect NKX3.1 from degradation. The effect of PTEN on NKX3.1 was mediated via rapid enzyme-substrate interaction. An effect of PTEN on gene transcription was seen , but not . In gene-targeted mice, Nkx3.1 expression significantly diminished shortly after loss of Pten expression in the prostate. Nkx3.1 loss primarily increased prostate epithelial cell proliferation . In these mice, mRNA was not affected by Pten expression. Thus, the prostate cancer suppressors PTEN and NKX3.1 interact and loss of PTEN is responsible, at least in part, for progressive loss of NKX3.1 that occurs during tumor progression. SIGNIFICANCE: PTEN functions as a phosphatase of NKX3.1, a gatekeeper suppressor of prostate cancer.
• Molina, A. M., Christos, P. J., Hackett, A., Nordquist, L. T., Gelmann, E. P., Stein, M. N., Sternberg, C. N., Beltran, H., Gracey, L., Galletti, G., Giannakakou, P., Nanus, D. M., & Tagawa, S. T. (2019). Abstract CT097: Phase I trial of apalutamide plus abiraterone acetate, docetaxel, and prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC). Cancer Research, 79. doi:10.1158/1538-7445.sabcs18-ct097
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  Background: Prostate cancer is driven by the androgen receptor (AR) pathway, which may be targeted by inhibition of androgen synthesis (e.g. abiraterone = Abi), AR signaling (e.g. apalutmide = Apa), and/or translocation of AR to the nucleus (e.g. docetaxel = Doce). The combination of AR inhibition plus taxane chemotherapy has already demonstrated clinical benefit (CHAARTED, STAMPEDE), lending weight to the theory that combining drugs targeting different points in the AR signaling pathway is effective. We hypothesize that the combination of Apa, Abi, and Doce will be safe and efficacious. Methods: Men with progressive mCRPC, intact organ function, and no prior exposure to Apa (ever) or Doce within 3 years were enrolled. Standard Abi 1000 mg daily, Doce 75 mg/m2 q3 weeks, and prednisone 5 mg BID was administered with different doses of Apa. Cohort 1 = Apa 120 mg daily, Cohort 2 = Apa 240 mg daily, Cohort 3 (if necessary) = Apa 180 mg daily in modified 3+3 design. The primary endpoint of the Phase I dose-escalation portion of the study was determination of dose-limiting toxicity (over 6 weeks) and recommended Phase II dose (RP2D). Results: Nine men (3 Apa 120 mg, 6 Apa 240 mg) with mCRPC and median age 69, median PSA 8.18 (range 0.07 - 278.5) were treated. 67% with bone, 78% LN, 11% lung, 11% other metastases. No DLT occurred with Apa 120 mg and 1 of 6 with Apa 240 mg had possibly related grade 3 hypertension. All had >95% PSA decline (78% with > 99% decline). Of 5 with measureable disease, 100% had RECIST response. 6 of 7 with post-treatment CTC counts were undetectable. Conclusions: The combination of apalutamide plus abiraterone, docetaxel, and prednisone at full doses is tolerable, with the RP2D of the regimen Apa 240 mg daily, Abi 1000 mg daily, docetaxel 75 mg/m2 q3 wks, and prednisone 5 mg BID. The combination appears to be associated with a high rate of PSA decline, measurable disease response, and CTC count control. Tumor tissue, plasma ctDNA, and CTCs are being collected for analysis. Enrollment to the expansion phase of study to further refine efficacy and toxicity at PCCTC sites is ongoing including assessment of response and resistance biomarkers [NCT02913196] Citation Format: Ana Molina, Paul Christos, Amy Hackett, Luke Nordquist, Edward Gelmann, Mark Stein, Cora Sternberg, Himisha Beltran, Lauren Gracey, Giuseppe Galletti, Paraskevi Giannakakou, David M. Nanus, Scott T. Tagawa. Phase I trial of apalutamide plus abiraterone acetate, docetaxel, and prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT097.
• Andrews, C., Fortier, B., Hayward, A., Lederman, R., Petersen, L., McBride, J., Petersen, D. C., Ajayi, O., Kachambwa, P., Seutloali, M., Shoko, A., Mokhosi, M., Hiller, R., Adams, M., Ongaco, C., Pugh, E., Romm, J., Shelford, T., Chinegwundoh, F., , Adusei, B., et al. (2018). Development, Evaluation, and Implementation of a Pan-African Cancer Research Network: Men of African Descent and Carcinoma of the Prostate. Journal of global oncology, 4, 1-14.
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  Cancer of the prostate (CaP) is the leading cancer among men in sub-Saharan Africa (SSA). A substantial proportion of these men with CaP are diagnosed at late (usually incurable) stages, yet little is known about the etiology of CaP in SSA.
• Leighton, X., Bera, A., Eidelman, O., Bubendorf, L., Zellweger, T., Banerjee, J., Gelmann, E. P., Pollard, H. B., & Srivastava, M. (2018). Tissue microarray analysis delineate potential prognostic role of Annexin A7 in prostate cancer progression. PloS one, 13(10), e0205837.
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  Annexin A7 (ANXA7) is a member of the multifunctional calcium or phospholipid-binding annexin gene family. While low levels of ANXA7 are associated with aggressive types of cancer, the clinical impact of ANXA7 in prostate cancer remains unclear. Tissue microarrays (TMA) have revealed several new molecular markers in human tumors. Herein, we have identified the prognostic impact of ANXA7 in a prostate cancer using a tissue microarray containing 637 different specimens.
• Neugut, A. I., & Gelmann, E. P. (2016). Treatment of the Prostate in the Presence of Metastases: Lessons from Other Solid Tumors. European urology, 69(5), 795-6.
• Zhang, H., Zheng, T., Chua, C. W., Shen, M., & Gelmann, E. P. (2016). Nkx3.1 controls the DNA repair response in the mouse prostate. The Prostate, 76(4), 402-8.
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  The human prostate tumor suppressor NKX3.1 mediates the DNA repair response and interacts with the androgen receptor to assure faithful completion of transcription thereby protecting against TMPRSS2-ERG gene fusion. To determine directly the effect of Nkx3.1 in vivo we studied the DNA repair response in prostates of mice with targeted deletion of Nkx3.1.
• Bowen, C., Zheng, T., & Gelmann, E. P. (2015). NKX3.1 Suppresses TMPRSS2-ERG Gene Rearrangement and Mediates Repair of Androgen Receptor-Induced DNA Damage. Cancer research, 75(13), 2686-98.
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  TMPRSS2 gene rearrangements occur at DNA breaks formed during androgen receptor-mediated transcription and activate expression of ETS transcription factors at the early stages of more than half of prostate cancers. NKX3.1, a prostate tumor suppressor that accelerates the DNA repair response, binds to androgen receptor at the ERG gene breakpoint and inhibits both the juxtaposition of the TMPRSS2 and ERG gene loci and also their recombination. NKX3.1 acts by accelerating DNA repair after androgen-induced transcriptional activation. NKX3.1 influences the recruitment of proteins that promote homology-directed DNA repair. Loss of NKX3.1 favors recruitment to the ERG gene breakpoint of proteins that promote error-prone nonhomologous end-joining. Analysis of prostate cancer tissues showed that the presence of a TMPRSS2-ERG rearrangement was highly correlated with lower levels of NKX3.1 expression consistent with the role of NKX3.1 as a suppressor of the pathogenic gene rearrangement.
• Song, L. N., Silva, J., Koller, A., Rosenthal, A., Chen, E. I., & Gelmann, E. P. (2015). The Tumor Suppressor NKX3.1 Is Targeted for Degradation by DYRK1B Kinase. Molecular cancer research : MCR, 13(5), 913-22.
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  NKX3.1 is a prostate-specific homeodomain protein and tumor suppressor whose expression is reduced in the earliest phases of prostatic neoplasia. NKX3.1 expression is not only diminished by genetic loss and methylation, but the protein itself is a target for accelerated degradation caused by inflammation that is common in the aging prostate gland. NKX3.1 degradation is activated by phosphorylation at C-terminal serine residues that mediate ubiquitination and protein turnover. Because NKX3.1 is haploinsufficient, strategies to increase its protein stability could lead to new therapies. Here, a high-throughput screen was developed using an siRNA library for kinases that mediate NKX3.1 degradation. This approach identified several candidates, of which DYRK1B, a kinase that is subject to gene amplification and overexpression in other cancers, had the greatest impact on NKX3.1 half-life. Mechanistically, NKX3.1 and DYRK1B were shown to interact via the DYRK1B kinase domain. In addition, an in vitro kinase assay showed that DYRK1B phosphorylated NKX3.1 at serine 185, a residue critical for NKX3.1 steady-state turnover. Lastly, small-molecule inhibitors of DYRK1B prolonged NKX3.1 half-life. Thus, DYRK1B is a target for enzymatic inhibition in order to increase cellular NKX3.1.
• Bowen, C., Ju, J. H., Lee, J. H., Paull, T. T., & Gelmann, E. P. (2013). Functional activation of ATM by the prostate cancer suppressor NKX3.1. Cell reports, 4(3), 516-29.
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  The prostate tumor suppressor NKX3.1 augments response to DNA damage and enhances survival after DNA damage. Within minutes of DNA damage, NKX3.1 undergoes phosphorylation at tyrosine 222, which is required for a functional interaction with ataxia telangiectasia mutated (ATM) kinase. NKX3.1 binds to the N-terminal region of ATM, accelerates ATM activation, and hastens the formation of γhistone2AX. NKX3.1 enhances DNA-dependent ATM kinase activation by both the MRN complex and H2O2 in a DNA-damage-independent manner. ATM, bound to the NKX3.1 homeodomain, phosphorylates NKX3.1, leading to ubiquitination and degradation. Thus, NKX3.1 and ATM have a functional interaction leading to ATM activation and then NKX3.1 degradation in a tightly regulated DNA damage response specific to prostate epithelial cells. These findings demonstrate a mechanism for the tumor-suppressor properties of NKX3.1, demonstrate how NKX3.1 may enhance DNA integrity in prostate stem cells and may help to explain how cells differ in their sensitivity to DNA damage.
• Lim, E., & Gelmann, E. P. (2013). Renal cell cancer treated with a single-edged sword. Cell reports, 3(2), 275-6.
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  Preclinical and early clinical data suggest that antiangiogenic treatments may lead to more aggressive tumors. In this issue of Cell Reports, Blagoev et al. (2013) show that sunitinib, a multikinase inhibitor with antiangiogenic effects, does not worsen the survival of patients with metastatic kidney cancer.
• Muhlbradt, E., Ma, J., Severi, G., Ortner, E., Hayes, V., Hoang, H. N., Stampfer, M., Giles, G., Pollak, M., & Gelmann, E. P. (2013). Variant NKX3.1 and Serum IGF-1: Investigation of Interaction in Prostate Cancer. Genes & cancer, 4(11-12), 535-45.
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  NKX3.1 is a tumor suppressor down-regulated in early prostate cancers. A SNP (rs2228013), which represents a polymorphic NKX3.1(C154T) coding for a variant protein NKX3.1(R52C), is present in 10% of the population and is related to prostatic enlargement and prostate cancer. We investigated rs2228013 in prostate cancer risk for 937 prostate cancer cases and 1,086 age-matched controls from a nested case-control study within the prospective Physicians' Health Study (PHS) and among 798 cases and 527 controls retrospectively collected in the Risk Factors for Prostate Cancer Study of the Victoria Cancer Council (RFPCS). We also investigated the interaction between serum IGF-I levels and NKX3.1 genotype in the populations from PHS and RFPCS. In the PHS, we found no overall association between the variant T allele in rs2228013 in NKX3.1 and prostate cancer risk (odd ratio = 1.25; 95% confidence interval = 0.92-1.71). A subgroup analysis for cases diagnosed before age 70 showed an increased risk (relative risk = 1.55; 95% confidence interval = 1.04-2.31) of overall prostate cancer. In this age-group, the risk of metastatic cancer at diagnosis or of fatal cancer was even higher in carriers of the T allele (relative risk = 2.15; 95% confidence interval = 1.00-4.63). These associations were not replicated in the RFPCS. Serum IGF-I levels were found to be a risk factor for prostate cancer in both study populations. The wild type NKX3.1 protein can induce IGFBP-3 expression in vitro. We report that variant NKX3.1 cannot induce IGFBP-3 expression, but the NKX3.1 genotype does not modify the association between serum IGF-I levels and prostate cancer risk.
• Song, L. N., Bowen, C., & Gelmann, E. P. (2013). Structural and functional interactions of the prostate cancer suppressor protein NKX3.1 with topoisomerase I. The Biochemical journal, 453(1), 125-36.
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  NKX3.1 (NK3 homeobox 1) is a prostate tumour suppressor protein with a number of activities that are critical for its role in tumour suppression. NKX3.1 mediates the cellular response to DNA damage by interacting with ATM (ataxia telangiectasia mutated) and by activation of topoisomerase I. In the present study we characterized the interaction between NKX3.1 and topoisomerase I. The NKX3.1 homeodomain binds to a region of topoisomerase I spanning the junction between the core and linker domains. Loss of the topoisomerase I N-terminal domain, a region for frequent protein interactions, did not affect binding to NKX3.1 as was shown by the activation of Topo70 (N-terminal truncated topoisomerase I) in vitro. In contrast, NKX3.1 interacts with the enzyme reconstituted from peptide fragments of the core and linker active site domains, but inhibits the DNA-resolving activity of the reconstituted enzyme in vitro. The effect of NKX3.1 on both Topo70 and the reconstituted enzyme was seen in the presence and absence of camptothecin. Neither NKX3.1 nor CPT (camptothecin) had an effect on the interaction of the other with topoisomerase I. Therefore the interactions of NKX3.1 and CPT with the linker domain of topoisomerase I are mutually exclusive. However, in cells the effect of NKX3.1 on topoisomerase binding to DNA sensitized the cells to cellular toxicity and the induction of apoptosis by low doses of CPT. Lastly, topoisomerase I is important for the effect of NKX3.1 on cell survival after DNA damage as topoisomerase knockdown blocked the effect of NKX3.1 on clonogenicity after DNA damage. Therefore NKX3.1 and topoisomerase I interact in vitro and in cells to affect the CPT sensitivity and DNA-repair functions of NKX3.1.
• Ruiz, C., Oeggerli, M., Germann, M., Gluderer, S., Stocker, H., Andreozzi, M., Thalmann, G. N., Cecchini, M. G., Zellweger, T., Stürm, S., Koivisto, P. A., Helin, H. J., Gelmann, E. P., Glass, A. G., Gasser, T. C., Terracciano, L. M., Bachmann, A., Wyler, S., Bubendorf, L., & Rentsch, C. A. (2012). High NRBP1 expression in prostate cancer is linked with poor clinical outcomes and increased cancer cell growth. The Prostate, 72(15), 1678-87.
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  We recently established the rationale that NRBP1 (nuclear receptor binding protein 1) has a potential growth-promoting role in cell biology. NRBP1 interacts directly with TSC-22, a potential tumor suppressor gene that is differently expressed in prostate cancer. Consequently, we analyzed the role of NRBP1 expression in prostate cancer cell lines and its expression on prostate cancer tissue microarrays (TMA).
• Abate-shen, C., Abate-shen, C., Meneses, A. A., Meneses, A. A., Kinkade, C. W., Kinkade, C. W., Mitrofanova, A., Mitrofanova, A., Lefebvre, C., Lefebvre, C., Chua, C. W., Chua, C. W., Castillo-martin, M., Castillo-martin, M., Shen, M. M., Shen, M. M., Califano, A., Califano, A., Gelmann, E. P., & Gelmann, E. P. (2011). Abstract SY22-01: Interrogating gene expression programs from preclinical analyses of genetically engineered mouse models. Cancer Research, 71. doi:10.1158/1538-7445.am2011-sy22-01
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  Our laboratories have been investigating novel mechanisms of cancer progression, as well as new therapeutic approaches for early intervention and treatment of advanced disease by integrating analyses of human clinical data with molecular and functional studies of genetically engineered mutant (GEM) mice. In our analyses of prostate cancer, we have generated GEM mice that recapitulate the entire spectrum of disease progression from preinvasive lesions, termed prostate intraepithelial neoplasia (PIN), to castration-resistant and metastatic disease, which are the lethal forms of the disease. These GEM models are based on perturbation of the Akt/mTOR and MAP kinase signaling pathways, which are often co-activated in human prostate cancer and which function synergistically to promote castration-resistant metastatic prostate cancer. We have found that combinatorial inhibition of these signaling pathways in GEM mice that display castration-resistant metastatic prostate cancer results in abrogation of primary tumors, improved survival and reduced metastasis. Using computational approaches for comparative analyses of large-scale gene expression profiling data for mouse and human prostate cancer, we have been assembling molecular networks, called interactomes, to elucidate conserved cancer pathways. We have been investigating the consequences of drugs perturbations on the transcriptional network with the ultimate goal of identifying new druggable targets. In summary, our comparative investigations of prostate cancer in humans and GEM mice have revealed promising new molecular targets and new therapuetic approaches for the treatment of human cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY22-01. doi:10.1158/1538-7445.AM2011-SY22-01
• Beildeck, M. E., Gelmann, E. P., & Byers, S. W. (2010). Cross-regulation of signaling pathways: an example of nuclear hormone receptors and the canonical Wnt pathway. Experimental cell research, 316(11), 1763-72.
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  Predicting the potential physiological outcome(s) of any given molecular pathway is complex because of cross-talk with other pathways. This is particularly evident in the case of the nuclear hormone receptor and canonical Wnt pathways, which regulate cell growth and proliferation, differentiation, apoptosis, and metastatic potential in numerous tissues. These pathways are known to intersect at many levels: in the intracellular space, at the membrane, in the cytoplasm, and within the nucleus. The outcomes of these interactions are important in the control of stem cell differentiation and maintenance, feedback loops, and regulating oncogenic potential. The aim of this review is to demonstrate the importance of considering pathway cross-talk when predicting functional outcomes of signaling, using nuclear hormone receptor/canonical Wnt pathway cross-talk as an example.
• Bowen, C., & Gelmann, E. P. (2010). NKX3.1 activates cellular response to DNA damage. Cancer research, 70(8), 3089-97.
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  The prostate-specific tumor suppressor homeodomain protein NKX3.1 is inactivated by a variety of mechanisms in the earliest phases of prostate carcinogenesis and in premalignant regions of the prostate gland. The mechanisms by which NKX3.1 exercises tumor suppression have not been well elucidated. Here, we show that NKX3.1 affects DNA damage response and cell survival after DNA damage. NKX3.1 expression in PC-3 prostate cancer cells enhances colony formation after DNA damage but has minimal effect on apoptosis. NKX3.1 also diminishes and regulates total cellular accumulation of gammaH2AX. Endogenous NKX3.1 in LNCaP cells localizes to sites of DNA damage where it affects the recruitment of phosphorylated ATM and the phosphorylation of H2AX. Knockdown of NKX3.1 in LNCaP cells attenuates the acute responses of both ATM and H2AX phosphorylation to DNA damage and their subnuclear localization to DNA damage sites. NKX3.1 expression enhances activation of ATM as assayed by autophosphorylation at serine 1981 and activation of ATR as assayed by phosphorylation of CHK1. An inherited mutation of NKX3.1 that predisposes to early prostate cancer and attenuates in vitro DNA binding was devoid of the ability to activate ATM and to colocalize with gammaH2AX at foci of DNA damage. These data show a novel mechanism by which a homeoprotein can affect DNA damage repair and act as a tumor suppressor.
• Gelmann, E. P., & Henshall, S. M. (2009). Clinically relevant prognostic markers for prostate cancer: The search goes on. Annals of Internal Medicine, 150(Issue 9). doi:10.7326/0003-4819-150-9-200905050-00014
• Gelmann, E. P. (2008). Complexities of prostate-cancer risk. New England Journal of Medicine, 358(Issue 9). doi:10.1056/nejme0708703
• Taplin, M., Manola, J., Oh, W. K., Kantoff, P. W., Bubley, G. J., Barb, D., Gelmann, E. P., Balk, S. P., Mantzoros, C. S., & Smith, M. R. (2008). A phase II study of mifepristone (RU-486) in castration-resistant prostate cancer, with a correlative assessment of androgen-related hormones.. BJU international, 101(9), 1084-9. doi:10.1111/j.1464-410x.2008.07509.x
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  To evaluate mifepristone (RU-486) in patients with castration-resistant prostate cancer (CRPC), with a correlative assessment of serum androgens and androgen metabolites.The androgen receptor (AR) is critical in the development and progression of prostate cancer, but available antiandrogens incompletely abrogate AR signalling. Mifepristone is a potent AR antagonist that functions by competing with androgen, preventing AR coactivator binding and by enhancing binding of AR corepressors. Patients with CRPC were treated with mifepristone 200 mg/day oral until disease progression. Testosterone, dihydrotestosterone (DHT), androstenedione, dihydroepiandrosterone sulphate and the testosterone metabolite 3 alpha-diol G, were measured at baseline and during therapy..Nineteen patients were enrolled between April and August 2005; they were treated for a median (range) of 85 (31-338) days. The median prostate-specific antigen (PSA) level at enrollment was 22.0 (3.0-937.2) ng/mL. No patient had a PSA response (>50% reduction in PSA). Six patients had stable disease for a median of 5.5 months. After 1 month, adrenal androgens were increased and testosterone and DHT increased by 91% and 80%, respectively, compared to baseline..Mifepristone had limited activity in patients with CRPC, and stimulated a marked increase in adrenal androgens, testosterone and DHT. We hypothesise that inhibition of glucocorticoid receptor by mifepristone resulted in an increase in adrenocorticotropic hormone and subsequent increase in adrenal androgens, and that their conversion by tumour cells to testosterone and DHT probably limited the efficacy of mifepristone. These data emphasize the continued importance of alternative androgen sources in AR signalling in CRPC.
• Schumacher, F. R., Feigelson, H. S., Cox, D. G., Haiman, C. A., Albanes, D., Calle, E. E., Chanock, S. J., Colditz, G. A., Diver, W. R., Dunning, A. M., Freedman, M. L., Gaziano, J. M., Giovannucci, E., Hankinson, S. E., Hayes, R. B., Henderson, B. E., Hoover, R. N., Kaaks, R., Kolonel, L. N., , Kraft, P., et al. (2007). A common 8q24 variant in prostate and breast cancer from a large nested case-control study.. Cancer research, 67(7), 2951-6. doi:10.1158/0008-5472.can-06-3591
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  Two recent studies independently identified polymorphisms in the 8q24 region, including a single nucleotide polymorphism (rs1447295), strongly associated with prostate cancer risk. Here, we replicate the overall association in a large nested case-control study from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium using 6,637 prostate cancer cases and 7,361 matched controls. We also examine whether this polymorphism is associated with breast cancer among 2,604 Caucasian breast cancer cases and 3,118 matched controls. The rs1447295 marker was strongly associated with prostate cancer among Caucasians (P = 1.23 x 10(-13)). When we exclude the Multiethnic Cohort samples, previously reported by Freedman et al., the association remains highly significant (P = 8.64 x 10(-13)). Compared with wild-type homozygotes, carriers with one copy of the minor allele had an OR(AC) = 1.34 (99% confidence intervals, 1.19-1.50) and carriers with two copies of the minor allele had an OR(AA) = 1.86 (99% confidence intervals, 1.30-2.67). Among African Americans, the genotype association was statistically significant in men diagnosed with prostate cancer at an early age (P = 0.011) and nonsignificant for those diagnosed at a later age (P = 0.924). This difference in risk by age at diagnosis was not present among Caucasians. We found no statistically significant difference in risk when tumors were classified by Gleason score, stage, or mortality. We found no association between rs1447295 and breast cancer risk (P = 0.590). Although the gene responsible has yet to be identified, the validation of this marker in this large sample of prostate cancer cases leaves little room for the possibility of a false-positive result.
• Coleman, I., Hawley, S., Gifford, D., Coleman, R., Beer, T. M., Hood, L., Nelson, P. S., Datta, M. W., Gelmann, E. P., Huang, C. Y., Knudsen, B. S., Lange, P. H., Lin, D. W., Mostaghel, E. A., True, L. D., & Vessella, R. L. (2006). A molecular correlate to the Gleason grading system for prostate adenocarcinoma.. Proceedings of the National Academy of Sciences of the United States of America, 103(29), 10991-6. doi:10.1073/pnas.0603678103
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  Adenocarcinomas of the prostate can be categorized into tumor grades based on the extent to which the cancers histologically resemble normal prostate glands. Because grades are surrogates of intrinsic tumor behavior, characterizing the molecular phenotype of grade is of potential clinical importance. To identify molecular alterations underlying prostate cancer grades, we used microdissection to obtain specific cohorts of cancer cells corresponding to the most common Gleason patterns (patterns 3, 4, and 5) from 29 radical prostatectomy samples. We paired each cancer sample with matched benign lumenal prostate epithelial cells and profiled transcript abundance levels by microarray analysis. We identified an 86-gene model capable of distinguishing low-grade (pattern 3) from high-grade (patterns 4 and 5) cancers. This model performed with 76% accuracy when applied to an independent set of 30 primary prostate carcinomas. Using tissue microarrays comprising >800 prostate samples, we confirmed a significant association between high levels of monoamine oxidase A expression and poorly differentiated cancers by immunohistochemistry. We also confirmed grade-associated levels of defender against death (DAD1) protein and HSD17 beta4 transcripts by immunohistochemistry and quantitative RT-PCR, respectively. The altered expression of these genes provides functional insights into grade-associated features of therapy resistance and tissue invasion. Furthermore, in identifying a profile of 86 genes that distinguish high- from low-grade carcinomas, we have generated a set of potential targets for modulating the development and progression of the lethal prostate cancer phenotype.
• Lamont, E. B., Herndon, J. E., Weeks, J. C., Henderson, I. C., Lilenbaum, R., Schilsky, R. L., Christakis, N. A., Atkins, J. N., Bartlett, N. L., Bloomfield, C. D., Budman, D. R., Cannelos, G. P., Citron, M., Clamon, G. H., Coltman, C., Comis, R. L., Crawford, J., Diasio, R. B., Drabeek, J. J., , Edelman, M. J., et al. (2005). Criterion validity of Medicare chemotherapy claims in Cancer and Leukemia Group B breast and lung cancer trial participants.. Journal of the National Cancer Institute, 97(14), 1080-3. doi:10.1093/jnci/dji189
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  To determine the accuracy with which Medicare claims data measure chemotherapy use in elderly Medicare beneficiaries with cancer, we performed a criterion validation study. We compared gold-standard clinical trial data for 175 elderly cancer patients treated in two Cancer and Leukemia Group B (CALGB) breast and lung cancer trials (i.e., 45 from trial 9344 and 130 from trial 9730) with contemporaneous ambulatory and in-patient Medicare health insurance claims data from Centers for Medicare and Medicaid Services (CMS). The breast trial participants studied were those elderly enrolled between 1995 and 1997 and treated with doxorubicin and cyclophosphamide or this combination with paclitaxel. The lung trial participants studied were those elderly enrolled between 1998 and 2000 and treated with paclitaxel and carboplatin or paclitaxel alone. Comparing CALGB data with Medicare claims, we found the crude sensitivity for chemotherapy administration was 93% (95% confidence interval [CI] = 88% to 96%). Individual chemotherapy agents had similarly high sensitivities, ranging from 81% (95% CI = 70% to 89%) for carboplatin to 91% (95% CI = 79% to 98%) for cyclophosphamide. Agent-specific specificities were 100%. CMS data reliably captured repeat administration of chemotherapy to within one cycle. Administrative Medicare claims data appear to be a valid source of information for chemotherapy administered to elderly Medicare beneficiaries with cancer.
• Li, H., Zhang, Y., Glass, A., Zellweger, T., Gehan, E., Bubendorf, L., Gelmann, E. P., & Nevalainen, M. T. (2005). Activation of signal transducer and activator of transcription-5 in prostate cancer predicts early recurrence. Clinical Cancer Research, 11(Issue 16). doi:10.1158/1078-0432.ccr-05-0562
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  Purpose: We have shown previously that the signal transducer and activator of transcription-5 (Stat5) is a critical survival factor in human prostate cancer cells. In addition, we recently showed that Stat5 is activated at a high level, particularly in high-grade human prostate cancers. Here, we investigated whether activation of Stat5 in prostate cancer was linked to clinical outcome with disease recurrence as end point. Experimental Design: Immunohistochemistry was used to detect active, nuclear Stat5 in 357 paraffin-embedded prostate cancer specimens on a tissue microarray with clinical follow-up data. Stat5 activation status in prostate cancer specimens was analyzed by univariate and multivariate survival analysis to determine whether activation of Stat5 predicts earlier prostate cancer recurrence. Separate sets of statistical analysis were done for all patients regardless of Gleason grade and for patients with prostate cancer of intermediate Gleason grades (3 and 4). Results and Conclusions: Stat5 activation in prostate cancer was associated with early disease recurrence (P = 0.0399). Importantly, active Stat5 also predicted shorter progression-free survival in intermediate Gleason grade prostate cancers (P = 0.0409). Stat5 activation remained an independent prognostic marker after adjusting for Gleason grade, pT stage, perineural invasion, or seminal vesicle infiltration in all patients (P = 0.0565) and in Gleason grade 3 or 4 patients (P = 0.0582). The results of this work also confirmed our previous finding of association of Stat5 activation with a high histologic grade of prostate cancer (R = 0.11, P = 0.033). In summary, our study shows that active Stat5 distinguished prostate cancer patients whose disease is likely to progress earlier; therefore, active Stat5 may be a useful marker for selection of more individualized treatment. The results of this study need to be validated in a large prospective cohort. © 2005 American Association for Cancer Research.
• Oken, M., Marcus, P., Hu, P., Beck, T., Hocking, W., Kvale, P., Cordes, J., Riley, T., Winslow, S., Peace, S., Levin, D., Prorok, P., Gohagan, J., Foauad, M., Oberman, A., Partridge, E., Urban, D., Higgins, D., Crawford, E., , Ogden, S., et al. (2005). Baseline chest radiograph for lung cancer detection in the randomized Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Journal of the National Cancer Institute, 97(24). doi:10.1093/jnci/dji430
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  Background: The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial was initiated in 1992 to examine cause-specific mortality reduction from screening for these four cancers in men and women. We report lung cancer detection results of the baseline screening round. Methods: Of the 154 942 participants enrolled, who were aged 55-74 years with no history of PLCO cancers, 77 465 were randomly assigned to the intervention arm. Current or former smokers and never smokers in this arm received an initial single-view posterior-anterior chest radiograph. Results: In the initial screen, 5991 (8.9%, 95% confidence interval [CI] = 8.7% to 9.2%) of radiographs were suspicious for lung cancer: 8.2% (95% CI = 7.9% to 8.5%) for women and 9.6% (95% CI = 9.3% to 10.0%) for men. Rates were highest for older age groups and for smokers. Among those 5991 participants with a positive screen, 206 (3.4%, 95% CI = 3.0% to 3.9%) underwent biopsy examination, 126 (61.2%, 95% CI = 54.5% to 67.8%) of whom were diagnosed with lung cancer within 12 months of the screen (59 in women and 67 in men). The positive predictive value was 2.1% (95% CI = 1.7% to 2.5%), and 1.9 lung cancers were detected per 1000 screens. Among these cancers, 44% (95% CI = 35% to 52%) were stage I non-small-cell lung cancer. High rates of lung cancer were found in current smokers (6.3 per 1000 screens) and in former smokers who had smoked within the past 15 years (4.9 per 1000 screens). The lung cancer detection rate among never smokers was 0.4 per 1000 screens; this group accounted for 11% (95% CI = 5.6% to 16.6%) of the cancers identified. Conclusions: In the baseline screen, nearly half the cancers were stage I. Whether this experience results in a reduction in lung cancer mortality is yet to be seen. © The Author 2005. Published by Oxford University Press. All rights reserved.
• Amin, A., Halabi, S., Gelmann, E. P., Small, E. J., Stadler, W. M., & Vogelzang, N. J. (2004). 9-Nitrocamptothecin as second line chemotherapy for men with progressive, metastatic, hormone refractory prostate cancer: Results of the CALGB 99901.. Urologic oncology, 22(5), 398-403. doi:10.1016/j.urolonc.2004.05.002
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  Institution of early hormone therapy in the PSA era coupled with demonstration of clinical benefit with chemotherapy in hormone refractory prostate cancer (HRPC) and acceptance of PSA decline as a surrogate for response has resulted in introduction of chemotherapy earlier in the natural history of disease. There now exists a need to identify, effective agents for second line chemotherapy. 9-nitrocamptothecin (9-NC) a novel, oral camptothecin analogue was tested as second line chemotherapy for patients with progressive hormone refractory prostate cancer..Eligible patients had metastatic hormone refractory prostate cancer with performance status (0-1) following progression on at least 1 prior cytotoxic chemotherapy. 9-NC was administered orally at the dose of 1.5 mg/m2/d for 5 days each week for 3 weeks, followed by rest for 1 week. Response was evaluated after 2 cycles according to the guidelines set forth for Phase II trials in HRPC by the PSA working group..Thirty-five patients were recruited to the study within a period of 6 months; 33 were evaluable for analysis. No patients had a >50% decline in PSA levels. Two out of 8 (25%) patients with measurable disease and 5/25 (20%) patients with nonmeasurable disease showed stable disease. The median time to disease and PSA progression was 2 months [95% confidence interval (CI), 0.9-2.8]. The median overall survival was 10 months (95% CI = 5-12). Seven patients are alive after a median follow-up of 23 months..9-nitrocamptothecin failed to elicit clinical or PSA responses. Further study in pretreated HRPC patients is not warranted.
• Coghlan, M., Gelmann, E. P., & Song, L. N. (2004). Antiandrogen effects of mifepristone on coactivator and corepressor interactions with the androgen receptor.. Molecular endocrinology (Baltimore, Md.), 18(1), 70-85. doi:10.1210/me.2003-0189
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  Mifepristone is a potent antagonist of steroid hormone receptors such as glucocorticoid and progesterone receptors. We investigated the potential for mifepristone to act as an antiandrogen and compared it with partial androgen receptor (AR) agonists and antagonists, in particular bicalutamide. Mifepristone was an effective antiandrogen in vitro that inhibited transcription from three androgen-responsive promoters and blocked the agonist R1881 in a dose-dependent manner. Like bicalutamide, mifepristone also antagonized the action of androgen receptor with a (T877A) mutation. Mifepristone competed effectively with R1881 with a relative binding affinity comparable to that of cyproterone acetate, and much higher than that of hydroxyflutamide and bicalutamide in a binding assay. Mifepristone could effectively induce the binding of the herpes simplex viral protein 16/AR fusion protein to the hormone response elements in the murine mammary tumor virus-luciferase reporter. With either wild-type or T877A mutant AR, mifepristone alone was unable to induce any detectable interaction with coactivators transcriptional intermediary factor-2 or beta-catenin but could inhibit the R1881-induced binding of AR to transcriptional intermediary factor-2 and beta-catenin. Similarly, mifepristone could inhibit the R1881-induced N/C-terminal interaction in a dose-dependent manner even though mifepristone alone has no effect on the N/C-terminal interaction of AR. We found that mifepristone could induce a strong interaction between AR and corepressors nuclear receptor corepressor and silencing mediator for retinoid and thyroid hormone receptors in both transactivation and two-hybrid assays to a greater degree than hydroxyflutamide, cyproterone acetate, and bicalutamide. The AR-corepressor interaction was also seen in coimmunoprecipitation assays. Finally, mifepristone at high concentrations induced a low level of prostate-specific antigen expression in LNCaP and antagonized prostate-specific antigen expression induced by R1881. Mifepristone also antagonized R1881 action on the growth of LNCaP prostate cancer cells.
• Herrell, R., Shah, S., Wilson, E. M., Gelmann, E. P., Byers, S. W., & Song, L. N. (2003). Beta-catenin binds to the activation function 2 region of the androgen receptor and modulates the effects of the N-terminal domain and TIF2 on ligand-dependent transcription.. Molecular and cellular biology, 23(5), 1674-87. doi:10.1128/mcb.23.5.1674-1687.2003
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  Beta-catenin is a multifunctional molecule that is activated by signaling through WNT receptors. beta-Catenin can also enhance the transcriptional activity of some steroid hormone receptors such as the androgen receptor and retinoic acid receptor alpha. Androgens can affect nuclear translocation of beta-catenin and influence its subcellular distribution. Using mammalian two-hybrid binding assays, analysis of reporter gene transcription, and coimmunoprecipitation, we now show that beta-catenin binds to the androgen receptor ligand-binding domain (LBD) and modulates the transcriptional effects of TIF2 and the androgen receptor N-terminal domain (NTD). In functional assays, beta-catenin bound to androgen receptor only in the presence of ligand agonists, not antagonists. Beta-catenin binding to the androgen receptor LBD was independent of and cooperative with the androgen receptor NTD and the p160 coactivator TIF2, both of which bind to the activation function 2 (AF-2) region of the androgen receptor. Different mutations of androgen receptor helix 3 amino acids disrupted binding of androgen receptor NTD and beta-catenin. beta-Catenin, androgen receptor NTD, and TIF2 binding to the androgen receptor LBD were affected similarly by a subset of helix 12 mutations, but disruption of two sites on helix 12 affected only binding of beta-catenin and not of TIF2 or the androgen receptor NTD. Mutational disruption of each of five LXXLL peptide motifs in the beta-catenin armadillo repeats did not disrupt either binding to androgen receptor or transcriptional coactivation. ICAT, an inhibitor of T-cell factor 4 (TCF-4), and E-cadherin binding to beta-catenin also blocked binding of the androgen receptor LBD. We also demonstrated cross talk between the WNT and androgen receptor signaling pathways because excess androgen receptor could interfere with WNT signaling and excess TCF-4 inhibited the interaction of beta-catenin and androgen receptor. Taken together, the data show that beta-catenin can bind to the androgen receptor LBD and modulate the effects of the androgen receptor NTD and TIF2 on transcription.
• Kimura, K., Markowski, M., Bowen, C., & Gelmann, E. (2001). Androgen blocks apoptosis of hormone-dependent prostate cancer cells. Cancer Research, 61(14).
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  Androgen plays a critical role in the promotion and growth of prostate cancer. Androgen ablation has an expanding role in prostate cancer treatment and is now used to improve the efficacy of radiation therapy in addition to its role in treatment of metastatic disease. Here we show that androgen interferes with induction of prostate cancer cell death induced by a variety of stimuli. The effect of androgen on cell death occurs predominantly by interference with caspase activation and the inhibition of caspase cleavage in both the extrinsic and intrinsic cell death pathways. Androgen inhibited apoptosis induced by both tumor necrosis factor α (TNF-α) and by Fas activation with or without concomitant irradiation. An antiapoptotic effect was seen in the presence of R1881, dihydrotestosterone, and also 17β-estradiol within 24 h of death induction. Sustained inhibition of apoptosis at 72 h was seen only with R1881, dihydrotestosterone, cyproterone acetate, and hydroxyflutamide. Androgen treatment inhibited activation of caspases-8, -7, and -9 by TNF-α +/- irradiation. Androgen attenuated BAX expression and blocked appearance of the proapoptotic p18 fragment of BAX. Androgen also abrogated BID cleavage induced by TNF-α + irradiation that contributed to a decrease in cytochrome c egress from mitochondria induced by TNF-α +/- irradiation. There was also decreased mitochondrial depolarization in response to TNF-α + irradiation. Production of the proapoptotic lipid metabolite ceramide was not affected by androgen, but androgen acted downstream from ceramide generation because R1881 blocked cell-death induction by bacterial sphingomyelinase. Inhibition of phosphoinositol-3-kinase activity by wortmannin induced apoptosis that was also blocked by androgen, but there was no effect on protein levels or phosphorylation of AKT, indicating that R1881 did not interact with survival signaling of phosphoinositol-3-kinase. Lastly, androgen inhibited activation of nuclear factor-κB during death induction, but the effect of androgen on cell death was not mediated by interference with the nuclear factor-κB pathway. The data suggest that androgen induced blockade of caspase activation in both intrinsic and extrinsic cell death pathways and thereby was able to protect prostate cancer cells from apoptosis induced by diverse stimuli.
• Kimura, K., Markowski, M., Bowen, C., & Gelmann, E. P. (2001). Androgen blocks apoptosis of hormone-dependent prostate cancer cells.. Cancer research, 61(14), 5611-8.
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  Androgen plays a critical role in the promotion and growth of prostate cancer. Androgen ablation has an expanding role in prostate cancer treatment and is now used to improve the efficacy of radiation therapy in addition to its role in treatment of metastatic disease. Here we show that androgen interferes with induction of prostate cancer cell death induced by a variety of stimuli. The effect of androgen on cell death occurs predominantly by interference with caspase activation and the inhibition of caspase cleavage in both the extrinsic and intrinsic cell death pathways. Androgen inhibited apoptosis induced by both tumor necrosis factor alpha (TNF-alpha) and by Fas activation with or without concomitant irradiation. An antiapoptotic effect was seen in the presence of R1881, dihydrotestosterone, and also 17beta-estradiol within 24 h of death induction. Sustained inhibition of apoptosis at 72 h was seen only with R1881, dihydrotestosterone, cyproterone acetate, and hydroxyflutamide. Androgen treatment inhibited activation of caspases-8, -7, and -9 by TNF-alpha +/- irradiation. Androgen attenuated BAX expression and blocked appearance of the proapoptotic p18 fragment of BAX. Androgen also abrogated BID cleavage induced by TNF-alpha + irradiation that contributed to a decrease in cytochrome c egress from mitochondria induced by TNF-alpha +/- irradiation. There was also decreased mitochondrial depolarization in response to TNF-alpha + irradiation. Production of the proapoptotic lipid metabolite ceramide was not affected by androgen, but androgen acted downstream from ceramide generation because R1881 blocked cell-death induction by bacterial sphingomyelinase. Inhibition of phosphoinositol-3-kinase activity by wortmannin induced apoptosis that was also blocked by androgen, but there was no effect on protein levels or phosphorylation of AKT, indicating that R1881 did not interact with survival signaling of phosphoinositol-3-kinase. Lastly, androgen inhibited activation of nuclear factor-kappaB during death induction, but the effect of androgen on cell death was not mediated by interference with the nuclear factor-kappaB pathway. The data suggest that androgen induced blockade of caspase activation in both intrinsic and extrinsic cell death pathways and thereby was able to protect prostate cancer cells from apoptosis induced by diverse stimuli.
• He, W. W., Sciavolino, P. J., Wing, J., Augustus, M., Hudson, P., Meissner, P. S., Curtis, R. T., Shell, B. K., Bostwick, D. G., Tindall, D. J., Gelmann, E. P., Abate-Shen, C., & Carter, K. C. (1997). A novel human prostate-specific, androgen-regulated homeobox gene (NKX3.1) that maps to 8p21, a region frequently deleted in prostate cancer. Genomics, 43(Issue 1). doi:10.1006/geno.1997.4715
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  We have isolated a prostate-specific gene (NKX3.1) in humans that is homologous to the Drosophila NK homeobox gene family. Northern blot analyses indicate that this gene is expressed at high levels in adult prostate and at a much lower level in testis, but is expressed little or not at all in several other tissues. In an androgen-dependent prostate carcinoma line, LNCaP, NKX3.1 mRNA is expressed at a basal level that was increased markedly upon androgen stimulation; the NKX3.1 mRNA was undetectable in several other human tumor cell lines including two androgen-independent prostate carcinoma lines. The NKX3.1 gene maps to chromosome band 8p21, a region frequently reported to undergo a loss of heterozygosity associated with tissue dedifferentiation and loss of androgen responsiveness during the progression of prostate cancer. Based on these data we propose that NKX3.1 is a candidate gene for playing a role in the opposing processes of androgen-driven differentiation of prostatic tissue and loss of that differentiation during the progression of prostate cancer.
• Voeller, H. J., Augustus, M., Madike, V., Bova, G. S., Carter, K. C., & Gelmann, E. P. (1997). Coding region of NKX3.1, a prostate-specific homeobox gene on 8p21, is not mutated in human prostate cancers.. Cancer research, 57(20), 4455-9.
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  Loss of heterozygosity at chromosome 8p21-22 is common in human prostate cancer, suggesting the presence of one or more tumor suppressor genes at this locus. A homeobox gene that is expressed specifically in adult human prostate, NKX3.1, the expression of which is regulated by androgen, maps to chromosome 8p21. Fine structure in situ mapping showed that NKX3.1 is proximal to MSR32 (macrophage scavenger receptor type II) and LPL (human lipoprotein lipase) and very close to NEFL (human neurofilament light chain) on 8p21. Single-strand conformational polymorphism analysis of 48 radical prostatectomy cancer specimens and 3 metastases for the entire coding region of NKX3.1 showed no tumor-specific sequence alterations in 50 specimens and total absence of the gene in 1 specimen known to have a biallelic deletion of 8p21. NKX3.1 was found to have a polymorphism at nucleotide 154 in codon 52 that resulted in a CGC-->TGC sequence change and an Arg-->Cys amino acid alteration (R52C). This polymorphism was present in 20% of DNA samples. If NKX3.1 is a target of the 8p21 LOH, it is not via disruption of the coding region of the gene.
• Voeller, H., Augustus, M., Madike, V., Bova, G., Carter, K., & Gelmann, E. (1997). Coding region of NKX3.1, a prostate-specific homeobox gene on 8p21, is not mutated in human prostate cancers. Cancer Research, 57(20).
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  Loss of heterozygosity at chromosome 8p21-22 is common in human prostate cancer, suggesting the presence of one or more tumor suppressor genes at this locus. A homeobox gene that is expressed specifically in adult human prostate, NKX3.1, the expression of which is regulated by androgen, maps to chromosome 8p21. Fine structure in situ mapping showed that NKX3.1 is proximal to MSR32 (macrophage scavenger receptor type II) and LPL (human lipoprotein lipase) and very close to NEFL (human neurofilament light chain) on 8p21. Single-strand conformational polymorphism analysis of 48 radical prostatectomy cancer specimens and 3 metastases for the entire coding region of NKX3.1 showed no tumor-specific sequence alterations in 50 specimens and total absence of the gene in 1 specimen known to have a biallelic deletion of 8p21. NKX3.1 was found to have a polymorphism at nucleotide 154 in codon 52 that resulted in a CGC→TGC sequence change and an Arg→Cys amino acid alteration (R52C). This polymorphism was present in 20% of DNA samples. If NKX3.I is a target of the 8p21 LOH, it is not via disruption of the coding region of the gene.
• Tricoli, J., Gumerlock, P., Yao, J., Chi, S., D'Souza, S., Nestok, B., DeVere White, R., French, F., Gelmann, E., Pretlow, T., & Stearns, M. (1996). Alterations of the retinoblastoma gene in human prostate adenocarcinoma. Genes Chromosomes and Cancer, 15(2). doi:10.1002/(sici)1098-2264(199602)15:2<108::aid-gcc5>3.0.co;2-7
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  The loss or mutational inactivation of the RB1 tumor suppressor gene has been implicated in the development of a diverse group of human malignancies. However, the contribution of the RB1 gene alteration to human prostatic carcinogenesis has been poorly understood. Thus far, deletion of the promoter sequence and exon 21 from one primary tumor specimen and the alterations found in the cell line DU-145, are the only cases of RB1 mutations reported in human carcinoma of the prostate. This study was designed to determine whether alterations in the structure or expression of the RB1 gene occur in human prostate carcinoma, and to determine the nature of these changes and the frequency with which they occur. One hundred twelve primary prostate tumor tissues and four metastatic lesions were obtained immediately after surgical resection. The RB1 gene was characterized in 68 tumor DNA samples using Southern analysis and the PG3.8M or H3-8 probes. Band profiles were analyzed by scanning densitometry. Sixty-three tumor DNA samples were analyzed for defects in the RB1 promoter using polymerase chain reaction (PCR) and heteroduplex analysis. Alterations in the expression of exons 1-27 were analyzed in 79 primary and four metastatic tumor RNAs using RT-PCR. Three of 68 tumors were identified to have gross rearrangement of the RB1 gene or deletion of one allele. One of four stage D tumor specimens showed truncated RT-PCR products indicating an internal deletion of RB1 transcripts. In all, 14 of 83 (17%) specimens displayed abnormally low levels of RB1 mRNA expression. Furthermore, these alterations of RB1 expression showed a correlation with increasing tumor stage and grade. These results suggest alterations of RB1 mRNA expression occur more frequently in higher stages and grades of prostate cancer and, thus, may be contributing to the malignant progression of a subset of human prostate cancer.
• Berchem, G. J., Bosseler, M., Sugars, L. Y., Voeller, H. J., Gelmann, E. P., Hj, V., Ly, S., & Zeitlin, S. G. (1995). Androgens induce resistance to bcl-2-mediated apoptosis in LNCaP prostate cancer cells.. Cancer research, 55(4), 735-8.
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  We describe an in vitro model for prostate cancer treatment that suggests a potential benefit for combined androgen ablation and cytotoxic chemotherapy. Androgen treatment of the LNCaP hormone-dependent human prostate cancer cell line induces increased expression of the BCL-2 protein. Increased levels of this protein are known to mediate inhibition of apoptosis. LNCaP cells, however, did not undergo apoptosis in response to androgen withdrawal. Etoposide exerts its cytotoxicity on LNCaP and other cells by inducing apoptosis. In vitro etoposide cytotoxicity was diminished 83% in the presence of either 10(-8) M dihydrotestosterone or 10(-9) M R1881 in LNCaP cells. The interaction between androgen and etoposide was mediated through the BCL-2 protein, since bcl-2 antisense oligonucleotides blocked the protective effect of androgens on etoposide cytotoxicity.
• Berchem, G., Bosseler, M., Sugars, L., Voeller, H., Zeitlin, S., & Gelmann, E. (1995). Androgens Induce Resistance to bcl-2-mediated Apoptosis in LNCaP Prostate Cancer Cells. Cancer Research, 55(4).
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  We describe an in vitro model for prostate cancer treatment that suggests a potential benefit for combined androgen ablation and cytotoxic chemotherapy. Androgen treatment of the LNCaP hormone-dependent human prostate cancer cell line induces increased expression of the BCL-2 protein. Increased levels of this protein are known to mediate inhibition of apoptosis. LNCaP cells, however, did not undergo apoptosis in response to androgen withdrawal. Etoposide exerts its cytotoxicity on LNCaP and other cells by inducing apoptosis. In vitro etoposide cytotoxicity was diminished 83% in the presence of either 10-8 M dihydrotestosterone or 10-9 M R1881 in LNCaP cells. The interaction between androgen and etoposide was mediated through the BCL-2 protein, since bcl-2 antisense oligonucleotides blocked the protective effect of androgens on etoposide cytotoxicity. © 1995, American Association for Cancer Research. All rights reserved.
• Sommers, C., Byers, S., & Gelmann, E. (1994). Alterations in β-Catenin Phosphorylation and Plakoglobin Expression in Human Breast Cancer Cells. Cancer Research, 54(13).
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  Because the cell adhesion molecule epithelial cadherin (E-cadherin) is absent in many invasive carcinomas, we transfected the E-cadherin gene into E-cadherin-negative, invasive breast cancer cell lines BT549 and HS578t to investigate the role of E-cadherin in invasive behavior. Although the transfected E-cadherin could mediate calcium-dependent aggregation to E-cadherin-transfected L-cells, morphology and invasiveness of the breast cancer cells were not altered. We investigated the strength of the linkage of the transfected E-cadherin to the actin cytoskeleton by examining the Triton X-100 solubility of the transfected E-cadherin. In BT549 and HS578t cells, a large proportion of the transfected E-cadherin was Triton soluble, whereas in E-cadherin-positive MCF-7 cells, Triton-insoluble E-cadherin was apparent at cell-cell borders. Interaction of E-cadherin with the actin cytoskeleton is thought to be mediated by the E-cadherin-binding proteins α-catenin, β-catenin, and plakoglobin. We found normal levels of α-catenin and β-catenin in BT549 and HS578t cells; however, low levels of plakoglobin were expressed in these cells compared to those found in weakly invasive MCF-7 cells. Furthermore, levels of tyrosine phosphorylation of β-catenin were elevated in E-cadherin-transfected BT549 and HS578t cells compared to MCF-7 cells. We conclude that other factors such as the expression and appropriate posttranslational modification of cadherin-associated proteins must be in place for E-cadherin to be fully functional, i.e., to alter invasiveness. During cancer progression, loss of E-cadherin expression itself or multiple other mechanisms that lead to loss of cell-cell adhesion (mutation, loss of catenin expression, alterations in phosphorylation) may contribute to a more metastatic phenotype. © 1994, American Association for Cancer Research. All rights reserved.
• Dawson, N. A., Wilding, G., Weiss, R. B., McLeod, D. G., Linehan, W. M., Frank, J. A., Jacob, J. L., & Gelmann, E. P. (1992). A pilot trial of chemohormonal therapy for metastatic prostate carcinoma. Cancer, 69(Issue 1). doi:10.1002/1097-0142(19920101)69:1<213::aid-cncr2820690135>3.0.co;2-v
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  Fifteen patients with previously untreated metastatic prostate cancer were treated on a pilot trial with a combination of maximal androgen blockade plus intermittent cytotoxic therapy after androgen priming to stimulate cell division. Androgen blockage was carried out using a gonadotropin‐releasing hormone analog (leuprolide) plus a nonsteroidal antiandrogen (flutamide). Carboplatin (CBDCA) (800 mg/m2) was given intravenously every 28 days, preceded for 3 days and followed for 3 days by androgen treatment with fluoxymesterone (5 mg orally twice a day), during which time flutamide was discontinued. Three patients (20%) achieved a complete response (CR), and eight patients (53.3%) achieved a partial response (PR). Four patients (26.7%) had stable disease (SD). The median progression‐free survival (PFS) time was 31 months. Nine of 15 patients (60%) remain alive with a median follow‐up time of 42+ months (range, 22 to 54 months). Grade 4 thrombocytopenia and Grades 3 or 4 leukopenia were experienced in 87% and 80% of patients, respectively, requiring dose reductions of CBDCA in 85% of the cycles. Six of 15 patients experienced a flare in bone pain with androgen priming. There were no associated spinal cord compressions; however, exclusion of impending spinal cord compression was required before entrance on study. Copyright © 1992 American Cancer Society
• Razzaque, A., Peters, S. M., Gelmann, E. P., Sheridan, M. J., & Rosenthal, L. J. (1991). Analysis of peripheral blood lymphocytes of AIDS and high-risk patients for human cytomegalovirus transforming DNA sequences. Intervirology, 32(Issue 1). doi:10.1159/000150180
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  Investigation into the presence of human cytomegalovirus (HCMV) transforming mtrII and mtrIII sequences in peripheral blood lymphocyte (PBL) specimens of AIDS and high-risk patients was carried out by nucleic acid hybridization analyses. These probes were selected because they were viral-specific and lacked homology to normal cellular DNAs. In Southern blot hybridizations carried out under stringent conditions, we detected HCMV mtrII sequences associated with the high-molecular-weight DNAs of PBLs in 17 of 37 patients either with AIDS/Kaposi’s sarcoma or at high risk for AIDS. In comparison, only 2 of 17 DNA specimens from PBLs of healthy blood donors showed hybridization to mtrII sequences. The inability to detect hybridization to the mtrIII region in most mtrII-positive specimens suggested a specific retention of mtrII sequences. Our study suggests that the retention of mtrII sequences in high molecular weight DNA may constitute a risk factor for the development/progression of AIDS. Alternatively, the retention of mtrII sequences may occur as a result of enhanced HCMV replication in patients with AIDS or at high risk for AIDS. © 1991 S. Karger AG, Basel.
• Sommers, C. L., Thompson, E. W., Torri, J. A., Kemler, R., Gelmann, E. P., & Byers, S. W. (1991). Cell adhesion molecule uvomorulin expression in human breast cancer cell lines: relationship to morphology and invasive capacities.. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research, 2(8), 365-72.
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  Loss of cell-cell adhesion in carcinoma cells may be an important step in the acquisition of an invasive, metastatic phenotype. We have examined the expression of the epithelial-specific cell adhesion molecule uvomorulin (E-cadherin, cell-CAM 120/80, L-CAM) in human breast cancer cell lines. We find that fibroblastoid, highly invasive, vimentin-expressing breast cancer cell lines do not express uvomorulin. Of the more epithelial-appearing, less invasive, keratin-expressing breast cancer cell lines, some express uvomorulin, and some do not. We examined the morphologies of the cell lines in the reconstituted basement membrane matrix Matrigel and measured the ability of the cells to traverse a Matrigel-coated filter as in vitro models for detachment of carcinoma cells from neighboring cells and invasion through basement membrane into surrounding tissue. Colonies of uvomorulin-positive cells have a characteristic fused appearance in Matrigel, whereas uvomorulin-negative cells appear detached. Cells which are uvomorulin negative and vimentin positive have a stellate morphology in Matrigel. We show that uvomorulin is responsible for the fused colony morphology in Matrigel since treatment of uvomorulin-positive MCF-7 cells with an antibody to uvomorulin caused the cells to detach from one another but did not induce invasiveness in these cells, as measured by their ability to cross a Matrigel-coated polycarbonate filter in a modified Boyden chamber assay. Two uvomorulin-negative, vimentin-negative cell lines are also not highly invasive as measured by this assay. We suggest that loss of uvomorulin-mediated cell-cell adhesion may be one of many changes involved in the progression of a carcinoma cell to an invasive phenotype.
• Sommers, C., Thompson, E., Torri, J., Kemler, R., Gelmann, E., & Byers, S. (1991). Cell adhesion molecule uvomorulin expression in human breast cancer cell lines: relationship to morphology and invasive capacities.. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research, 2(8).
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  Loss of cell-cell adhesion in carcinoma cells may be an important step in the acquisition of an invasive, metastatic phenotype. We have examined the expression of the epithelial-specific cell adhesion molecule uvomorulin (E-cadherin, cell-CAM 120/80, L-CAM) in human breast cancer cell lines. We find that fibroblastoid, highly invasive, vimentin-expressing breast cancer cell lines do not express uvomorulin. Of the more epithelial-appearing, less invasive, keratin-expressing breast cancer cell lines, some express uvomorulin, and some do not. We examined the morphologies of the cell lines in the reconstituted basement membrane matrix Matrigel and measured the ability of the cells to traverse a Matrigel-coated filter as in vitro models for detachment of carcinoma cells from neighboring cells and invasion through basement membrane into surrounding tissue. Colonies of uvomorulin-positive cells have a characteristic fused appearance in Matrigel, whereas uvomorulin-negative cells appear detached. Cells which are uvomorulin negative and vimentin positive have a stellate morphology in Matrigel. We show that uvomorulin is responsible for the fused colony morphology in Matrigel since treatment of uvomorulin-positive MCF-7 cells with an antibody to uvomorulin caused the cells to detach from one another but did not induce invasiveness in these cells, as measured by their ability to cross a Matrigel-coated polycarbonate filter in a modified Boyden chamber assay. Two uvomorulin-negative, vimentin-negative cell lines are also not highly invasive as measured by this assay. We suggest that loss of uvomorulin-mediated cell-cell adhesion may be one of many changes involved in the progression of a carcinoma cell to an invasive phenotype.
• Halverson, D., Modi, W., Dean, M., Gelmann, E., Dunn, K., Clanton, D., Oskarsson, M., O'Brien, S., & Blair, D. (1990). An oncogenic chromosome 8-9 gene fusion isolated following transfection of human ovarian carcinoma cell line DNA. Oncogene, 5(7).
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  Transfection of NIH3T3 cells with genomic DNA from the human ovarian adenocarcinoma tumor cell line OVCAR-3 identified ovc, a rearranged human DNA sequence which was generated during transfection and which induced both morphological transformation and tumorigenesis. A human alu repeat positive 10.5kb EcoRI fragment present in all transformants was cloned, and two alu-free fragments of 1.8 kb and 2.2 kb were subcloned. The cloned 10.5kb fragment is not biologically active in DNA transfection assays. Probe from the 2.2 kb fragment hybridizes to poly A+ RNA from the transformants and several human tumor cell lines, including OVCAR-3. The 2.2 kb fragment maps to a site on human chromosome 9 (9p24) not known to contain oncogenic sequences, and identifies a two allele polymorphic restriction site. The 1.8kb fragment maps to human chromosome 8. The ovc transforming sequences fail to hybridize to probes to any of 14 known oncogenes, indicating that they may represent a previously unknown human transforming gene.
• Wilding, G., Chen, M., & Gelmann, E. P. (1989). Aberrant response in vitro of hormone‐responsive prostate cancer cells to antiandrogens. The Prostate, 14(Issue 2). doi:10.1002/pros.2990140204
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  Antiandrogens are in use alone and in combination with other agents as hormonal therapy for prostate cancer. We conducted studies on the androgen‐responsive human prostate cancer cell line LNCaP to determine the direct effects of three antiandrogens (hydroxyflutamide, RU23908, and cyproterone acetate) on hormone‐responsive human prostate cancer cells in culture. Dihydrotestosterone (DHT) stimulated the growth of LNCaP cells in a dose‐dependent fashion. These cells contained approximately 31,000 high‐affinity (Kd = 9 × 10−10 M) androgen binding sites per cell. In the absence of any androgenic stimulation, all three antiandrogens tested showed agonistic properties by increasing the cell number and uptake of [3H]‐thymidine. Competitive uptake studies using [3H]‐R1881, a nonmetabolized androgen, showed that the three antiandrogens inhibited specific R1881 uptake with IC50s of 0.9 × 10−7 M for hydroxyflutamide, 2 × 10−7 M for RU23908, and 1 × 10−7 M for cyproterone acetate. It is not known whether these unexpected agonistic effects are due to an altered receptor, previously unmasked agonistic properties of the antiandrogens, or emergence of a hypersensitive clone of cells. Copyright © 1989 Wiley‐Liss, Inc., A Wiley Company
• Freter, C. E., Lippman, M. E., Cheville, A., Zinn, S., & Gelmann, E. P. (1988). Alterations in phosphoinositide metabolism associated with 17 β-estradiol and growth factor treatment of MCF-7 breast cancer cells. Molecular Endocrinology, 2(Issue 2). doi:10.1210/mend-2-2-159
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  Steady-state levels of phosphatidyl inositol (Ptdlns) turnover are examined in MCF-7 human breast cancer cells in response to estradiol treatment. Elevated levels of Ptdlns are observed 12-24 h after estradiol treatment, occur at estradiol concentrations as low as 10-12 m, and are competitively blocked by the antiestrogen LY117018. MCF-7 cells secrete a transforming growth factor (TGF) α-like material which can partly replace estradiol in conferring tumorgen-icity in nude mice. We show that acute or chronic treatment of MCF-7 cells with TGFα results in elevated Ptdlns turnover and that chronic treatment increases growth rate. In contrast TGFβ is growth inhibitory and blocks estradiol-induced increases in Ptdlns turnover. A phosphatidyl inositol 4, 5-bisphos-phate specific phospholipase-C activity has been identified and is elevated in association with estradiol treatment. These data are consistent with estradiol-induced autocrine growth factors, including TGFα, acting through the Ptdlns turnover pathway as part of their mechanism of action. © 1988 by The Endocrine Society.
• Zajac-Kaye, M., Gelmann, E. P., & Levens, D. (1988). A point mutation in the c-myc locus of a burkitt lymphoma abolishes binding of a nuclear protein. Science, 240(Issue 4860). doi:10.1126/science.2454510
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  A 20-base pair region in the first intron of the human c-myc gene was identified as the binding site of a nuclear protein. This binding site is mutated hi five out of seven Burkitt lymphomas sequenced to date. To investigate the protein-recognition region in greater detail, the abnormal c-myc allele from a Burkitt lymphoma line (PA682) that carries a t(8;22) chromosomal translocation was used. A point mutation in the binding region of the PA682 c-myc DNA abolished binding of this nuclear protein. This protein may be an important factor for control of c-myc expression, and mutations in its recognition sequence may be associated with c-myc activation in many cases of Burkitt lymphoma.
• Dickson, R. B., Kasid, A., Huff, K. K., Bates, S. E., Knabbe, C., Bronzert, D., Gelmann, E. P., & Lippman, M. E. (1987). Activation of growth factor secretion in tumorigenic states of breast cancer induced by 17β-estradiol or v-Ha-ras oncogene. Proceedings of the National Academy of Sciences of the United States of America, 84(Issue 3). doi:10.1073/pnas.84.3.837
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  The MCF-7 human breast cancer cell line responds to estrogen stimulation in vitro by increased secretion of growth factors and proliferation and in vivo by tumor formation in the nude mouse. To test a possible role of growth factor secretion in expression of the tumorigenic phenotype, we stably transfected MCF-7 cells with the v-Ha-ras oncogene to produce the MCF-7ras cell line. The MCF-7ras cell line was tumorigenic in the absence of estrogens and secreted 3- to 5-fold elevated levels of a high molecular weight form of a type α transforming growth factor-like growth factor, type β transforming growth factor, and insulin-like growth factor I. MCF-7ras cells, in contrast to MCF-7, were less sensitive to further growth stimulation by estrogen, type α transforming growth factor, and insulin-like growth factor I and showed little change in receptor levels for these hormones. Conditioned medium from MCF-7ras cells as well as two of its component growth factors (insulin-like growth factor I and type α transforming growth factor) replaced estrogen in stimulating MCF-7 colony formation in vitro. A coordinate increase in growth factor secretion by human breast cancer may contribute to its escape from estrogen dependence.
• Gelmann, E. P., Longo, D., Clifford Lane, H., Fauci, A. S., Masur, H., Wesley, M., Preble, O. T., Jacob, J., & Steis, R. (1987). Combination chemotherapy of disseminated kaposi's sarcoma in patients with the acquired immune deficiency syndrome. The American Journal of Medicine, 82(Issue 3). doi:10.1016/0002-9343(87)90445-1
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  Two clinical trials were conducted to assess the efficacy and safety of a combination chemotherapy regimen for the treatment of Kaposi's sarcoma in patients with the acquired immune deficiency syndrome (AIDS). Eighteen consecutive patients with disseminated Kaposi's sarcoma were treated with a six-drug regimen of doxorubicin (Adriamycin), vinblastine, bleomycin/actinomycin D, vincristine, dacarbazine (ABV/ADV). A brief partial or complete response was achieved in 13 patients. Most patients died of opportunistic infections. Eighteen consecutive patients with disseminated Kaposi's sarcoma were then randomly assigned to therapy with either recombinant alpha interferon or ABV/ADV. The treatment responses in these two groups were comparable to results of earlier trials, and the incidence of opportunistic infections during therapy did not differ between the two treatment arms. It is concluded that chemotherapy is effective and safe for use in palliative management of Kaposi's sarcoma in patients with AIDS. © 1987.
• Andriole, G., Macher, A., Reichert, C., Masur, H., Gelmann, E., & Linehan, W. (1986). AIDS. Case for diagnosis, 1986. Military Medicine.. Military medicine, 151(8).
• Lippman, M., Dickson, R., Kasid, A., Gelmann, E., Davidson, N., McManaway, M., Huff, K., Bronzert, D., Bates, S., Swain, S., & Knabbe, C. (1986). Autocrine and paracrine growth regulation of human breast cancer. Journal of Steroid Biochemistry, 24(1). doi:10.1016/0022-4731(86)90044-0
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  Previous work from our laboratory has demonstrated that human breast cancer (BC) cells in culture can be stimulated by physiologic concentrations of estrogen. In an effort to further understand this process, we have examined the biochemical and biological properties of proteins secreted by human BC cells in vitro. We have developed a defined medium system which simultaneously allows the collection of factors secreted by the BC cells, facilitates their purification and allows for an unequivocal assay of their effect on other BC cells. By both biochemical and radioimmunoassay procedures, MCF-7 cells secrete large quantities of IGF-I-like activity. The cells contain receptors for IGF-I and are stimulated by physiologic concentrations of IGF-I. Multiple additional peaks of growth stimulatory activity can be obtained by partial purification of conditioned media from human BC cells by sequential dialysis, acid extraction and Biogel P60 chromatography. These peaks are induced up to 200-fold by physiologic concentrations of estrogen. Several of these peaks cross-react in a radioreceptor assay with EGF and are thus candidates for transforming growth factors. Monoclonal antibodies (MCA) have been prepared which react with secreted proteins from the MCF-7 cells. One of these MCAs binds to material from MCF-7 and ZR-75-1 hormone-dependent BC cells only when these two lines are treated with estrogen but reacts with conditioned medium from several other hormone-independent cell lines in the absence of estrogen stimulation. This MCA is currently undergoing further characterization and evaluation of its biological potency. We conclude that with estrogen stimulation, hormone-dependent human BC cells secrete peptides which when partially purified can replace estrogen as a mitogen. Their role as autocrine or paracrine growth factors and their effects on surrounding nonneoplastic stroma may suggest a means of interfering with tumor proliferation. © 1986.
• Yarchoan, R., Weinhold, K. J., Lyerly, H. K., Gelmann, E., Blum, R. M., Shearer, G. M., Mitsuya, H., Collins, J. M., Myers, C. E., Klecker, R. W., Markham, P. D., Durack, D. T., Lehrman, S. N., Barry, D. W., Fischl, M. A., Gallo, R. C., Bolognesi, D. P., & Broder, S. (1986). ADMINISTRATION OF 3'-AZIDO-3'-DEOXYTHYMIDINE, AN INHIBITOR OF HTLV-III/LAV REPLICATION, TO PATIENTS WITH AIDS OR AIDS-RELATED COMPLEX. The Lancet, 327(Issue 8481). doi:10.1016/s0140-6736(86)92808-4
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  In a 6-week clinical trial 4 dose regimens of 3'-azido-3'-deoxythymidine (AZT), a thymidine analogue with potent anti-viral activity against HTLV-III in vitro, were examined in 19 patients with the acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC). AZT was given intravenously for 2 weeks, then orally for 4 weeks at twice the intravenous dose. AZT was well absorbed from the gut and crossed the bloodbrain barrier. Therapeutic levels were maintained with 5 mg given intravenously or 10 mg given orally every 4 h. Treatment was not limited by side-effects, the commonest of which were headaches and depression of white-cell counts. 15 of the 19 patients had increases in their numbers of circulating helper-inducer T lymphocytes (p
• Clifford Lane, H., Masur, H., Gelmann, E., Longo, D., Steis, R., Chused, T., Whalen, G., Edgar, L., & Fauci, A. (1985). Correlation between immunologic function and clinical subpopulations of patients with the acquired immune deficiency syndrome. The American Journal of Medicine, 78(3). doi:10.1016/0002-9343(85)90332-8
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  The present study was designed to determine whether there was a significant correlation between the clinical presentation of patients with AIDS or AIDS-related illnesses and the degree of their underlying immunologic abnormalities. In 17 patients who presented with opportunistic infections, the mean number of T4 lymphocytes was 34/mm3 and the mean proliferative response to phytohemagglutinin 26,000 cpm; in 12 patients who presented with Kaposi's sarcoma alone, the mean number of T4 cells was 231/mm3 and the mean proliferative response to phytohemagglutinin, 32,809 cpm; and in nine patients with the lymphadenopathy syndrome, the mean number of T4 cells was 703/mm3 and the mean proliferative response to phytohemagglutinin, 49,317 cpm. These findings suggest that those patients who present with opportunistic infections as their initial clinical manifestation of AIDS may represent a subgroup with a more severe immunologic derangement prior to clinical diagnosis. Thus, In those who have a predisposition to Kaposi's sarcoma, this disease will often develop, prior to the development of T cell dysfunction, to the degree of that in those who present with opportunistic infections. This finding is of importance in attempts to understand the pathogenesis of this syndrome and in the design of therapeutic trials. © 1985.
• Kleinerman, E. S., Ceccorulli, L. M., Zwelling, L. A., Twilley, T., Herberman, R. B., Jacob, J., & Gelmann, E. P. (1985). Activation of monocyte-mediated tumoricidal activity in patients with acquired immunodeficiency syndrome. Journal of Clinical Oncology, 3(Issue 7). doi:10.1200/jco.1985.3.7.1005
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  The purpose of these studies was to determine whether peripheral blood monocytes from acquired immunodeficiency syndrome (AIDS) patients with Kaposi's sarcoma could be activated to lyse human tumor target cells in vitro. Monocytes were isolated and incubated for 24 hours in vitro with either medium (control), a crude mitogen-induced lymphokine preparation (MAF), or endotoxin before the addition of [125I]IUdR-labeled A375 melanoma target cells. Cytolysis was determined 72 hours later. Twelve (100%) of 12 patients tested had monocyte-mediated cytotoxicity values that were comparable to those of normal individuals. Recombinant human gamma interferon (IFN(γ)) activated both normal and AIDS monocyte-mediated tumoricidal function only when combined with lipopolysaccharide (LPS). In addition, mononuclear cells from 10 AIDS patients were also tested for their ability to secrete MAF and IFN(γ) in response to a mitogenic stimulus. Lymphokines generated from all 10 patients contained substantial amounts of IFN(γ) (100 to 2,500 U/mL); however, 3 of these 10 lymphokine preparations failed to activate normal monocytes to lyse tumor cells. These results suggest that monocyte-mediated tumoricidal function of AIDS patients is intact and thus suggest new approaches for the therapy of AIDS.
• Boccia, R., Gelmann, E., Baker, C., Marti, G., & Longo, D. (1984). A hemolytic-uremic syndrome with the acquired immunodeficiency syndrome. Annals of Internal Medicine, 101(5). doi:10.7326/0003-4819-101-5-716_2
• Gelmann, E. P., Burny, A., & Kettmann, R. (1984). Characterization of cellular sequences flanking an integrated bovine leukemia virus genome. Journal of Virology, 52(Issue 3). doi:10.1128/jvi.52.3.988-990.1984
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  We cloned a 20.2-kilobase fragment, including the unique proviral integration site, from the tumor tissue DNA of a bovine leukemia virus-induced lymphoma (tumor 1351). This clone contained 5.5 kilobases of flanking sequences at either side of the full-length integrated viral genome. Hybridization analysis of both 3' and 5' cellular flanking regions provided no evidence for rearrangements at this locus in other tumors, RNA transcription from either flanking region, or homology to eight known onc genes.
• Gelmann, E. P., Clanton, D. J., Jariwalla, R. J., & Rosenthal, L. J. (1983). Characterization and location of myc homologous sequences in human cytomegalovirus DNA. Proceedings of the National Academy of Sciences of the United States of America, 80(Issue 16 I). doi:10.1073/pnas.80.16.5107
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  Specific DNA fragments from human cytomegalovirus (HCMV) strains Towne and AD169 exhibited homology to myc DNA sequences under hybridization conditions corresponding to a 22-28% base mismatch. In a specific subset of hybridizing HCMV fragments, the homology was restricted to the 5' half of viral v-myc and the 5' half of human c-myc. No hybridization was observed between HCMV fragments and the 3' v-myc and 3' human c-myc probes. In Towne DNA, myc homologous sequences mapped in four regions within the long unique segment (0.070-0.094, 0.134-0.156, 0.454-0.470, and 0.591-0.605 map unit) and one region in each of the short terminal repeats (0.832-0.847 and 0.984-1.0 map unit). In strain AD169, myc homology mapped in three regions within the long unique segment (0.123-0.147, 0.174-0.198, and 0.583-0.606 map unit) and one region in each of the short terminal repeats (0.833-0.863 and 0.976-1.0 map unit). By utilizing probes specific for the 5' and 3' portions of v-myc and human c-myc, we established that the regions of homology in a specific subset of HCMV restriction fragments corresponded to the 5' half of myc and were not due to MC29 viral helper sequences, flanking cellular sequences, or binding of probe to G-C-rich DNA.
• Josephs, S. F., Favera, R. D., & Gelmann, E. P. (1983). 5' Viral and human cellular sequences corresponding to the transforming gene of simian sarcoma virus. Science, 219(Issue 4584). doi:10.1126/science.6297002
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  The 5' nucleotide sequences of the transforming gene of simian sarcoma virus (v-sis) and its human cellular homolog (c-sis) were compared. A short homology was found between helper virus and cellular DNA sequences at the junction of v-sis and c-sis, which may have had a role in the original recombination event leading to the generation of simian sarcoma virus.
• Wong-Staal, F., Hahn, B., Manzari, V., Colombini, S., Franchini, G., Gelmann, E. P., & Gallo, R. C. (1983). A survey of human leukaemias for sequences of a human retrovirus. Nature, 302(Issue 5909). doi:10.1038/302626a0
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  Human T-cell leukaemia-lymphoma virus (HTLV) is an exogenous human retrovirus distinct from all known animal retroviruses. HTLV is closely linked to a subtype of adult T-cell malignancies and except for isolated cases, has not been found associated with any other form of leukaemia, lymphoma or other cancers (see refs 1, 2 for review). HTLV can be transmitted to cord blood T lymphocytes in vitro and the infected cells exhibit characteristics of transformed neoplastic T cells3-5. We have recently cloned DNA sequences derived from approximately 1 kilobase (kb) of the 5′ and 3′ termini of the HTLV genome, as well as a 4-5-kb defective HTLV provirus flanked by cellular sequences6. The availability of these probes has enabled us to carry out a limited survey of different fresh or cultured cells from patients of different lymphoid and myeloid malignancies for HTLV-related DNA sequences. The results presented here show that cells from all Japanese patients with adult T-cell leukaemia and several patients with various mature T-cell malignancies from elsewhere contained one or more copies of a highly conserved HTLV genome. The infected cells are of clonal origin. Fresh cells from 1 of the 10 myeloid leukaemic patients contained exogenous DNA sequences distantly related to HTLV. © 1983 Nature Publishing Group.
• Wong-Staal, F., Josephs, S., Dalla-Favera, R., Westin, E., Gelmann, E., Franchini, G., & Gallo, R. (1983). Cellular onc genes: their role as progenitors of viral onc genes and their expression in human cells.. Haematology and blood transfusion, 28(Issue). doi:10.1007/978-3-642-68761-7_38
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  Viral transforming (v-onc) genes are derived from cellular (c-onc) genes that are highly conserved among vertebrates. Comparative studies of v-onc and c-onc genes have shed some light on the mechanism leading to formation of the transforming viruses. A specific example of the sis gene is presented here for illustration. Studies on the expression of six c-onc genes in human cells revealed at least three categories of onc genes: (a) those that are universally expressed and probably are important in basic cellular functions, (b) those that are not detectably expressed in the cells examined and may have very transient expression in development, and (c) those that are only expressed in specific cell types and may be important in tissue differentiation. Our studies do not show conclusively a role of these onc genes in human neoplasias.
• Dalla-Favera, R., Gelmann, E. P., Martinotti, S., Franchini, G., Papas, T. S., Gallo, R. C., & Wong-Staal, F. (1982). Cloning and characterization of different human sequences related to the onc gene (v-myc) of avian myelocytomatosis virus (MC29). Proceedings of the National Academy of Sciences of the United States of America, 79(Issue 21 I). doi:10.1073/pnas.79.21.6497
• Gelmann, E., Anderson, T., Jaffe, E., & Broder, S. (1982). Chemotherapy for Lymphoma in a Patient With Common Variable Immunodeficiency: Case Report, Literature Review, and Recommendations for Chemotherapy in Immunodeficient Patients. Archives of Internal Medicine, 142(Issue 1). doi:10.1001/archinte.1982.00340140092017
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  A man with long-standing common variable hypogammaglobulinemia was treated with chemotherapy and local radiation for diffuse mixed lymphoma. He continues in complete remission 42 months after the completion of therapy. Vigorous therapy for lymphoma can be used in the face of preexistent immunodeficiency. Complete staging and appropriate combination chemotherapy or radiation therapy should be carried out for lymphomas that occur in certain immunodeficient patients. © 1982, American Medical Association. All rights reserved.
• Favera, R. D., Gelmann, E. P., Gallo, R. C., & Wong-staal, F. (1981). A human onc gene homologous to the transforming gene (v-sis) of simian sarcoma virus. Nature, 292(Issue 5818). doi:10.1038/292031a0
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  The human genome contains a single and constant locus (c-sis) related to the transforming gene (v-sis) of simian sarcoma virus. The isolation of a recombinant phage containing the entire human c-sis gene has allowed the study of its genomic organization: c-sis extends over a region of ∼12 kilobases (kb) which includes 1.2 kb of v-sis-related sequences interrupted by four intervening sequences. © 1981 Nature Publishing Group.
• Gelmann, E., Kaplan, H., & Declève, A. (1978). Biological and biochemical differences among ecotropic C-type RNA viral isolates chemically induced from C57BL/Ka mouse embryo cells in vitro. Virology, 85(1). doi:10.1016/0042-6822(78)90424-5
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  Several biological properties of the ecotropic viruses isolated after IUdR induction of C57BL/Ka mouse embryo cells in vitro were found to vary depending on the type of cell from which the viruses were recovered and their passage history in culture. The majority of the induced viral isolates were N-tropic. They could be separated into two classes on the basis of their XC plaque-forming ability and their electrophoretic mobility in SDS-polyacrylamide gels. The exogenous transfer to and propagation in C57BL/Ka fibroblasts of one N-tropic parent virus led to the appearance of a progeny virus population with N- and B-tropic activity and high plaque-forming ability. This preparation, which had B- and N-tropic activity, was either a heterogeneous mixture of N- and B-tropic particles or a heterozygote particle which contained N- and B-tropic genomes. After passage of limiting dilutions of that preparation in C57BL fibroblasts, a novel B-tropic virus was recovered which was distinct from other B-tropic fibrotropic viruses isolated previously from strain C57BL/Ka mice. This new isolate is believed to have originated from recombinational events which had taken place between the B-tropical viral genome endogenous to the C57BL/Ka fibroblasts and the exogenous N-tropic virus used to infect these cells. © 1978.
• Gelmann, E., & Steward, J. (1975). Admissions interviews. Journal of Medical Education, 50(11).
• Cronan, J., & Gelmann, E. (1973). An estimate of the minimum amount of unsaturated fatty acid required for growth of Escherichia coli.. Journal of Biological Chemistry, 248(4). doi:10.1016/s0021-9258(19)44280-4