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Dickkopf-1 Can Lead to Immune Evasion in Metastatic Castration-Resistant Prostate Cancer

Wise, David R; Schneider, Jeffrey A; Armenia, Joshua; Febles, Victor Adorno; McLaughlin, Bridget; Brennan, Ryan; Thoren, Katie L; Abida, Wassim; Sfanos, Karen S; De Marzo, Angelo M; Yegnasubramanian, Srinivasan; Fox, Josef J; Haas, Michael; Heath, Heidi; Kagey, Michael H; Newman, Walter; Sirard, Cynthia A; Fleisher, Martin; Morris, Michael J; Chen, Yu; Larson, Steven M; Haffner, Michael C; Nelson, Peter S; Schultz, Nikolaus; Garabedian, Michael J; Scher, Howard I; Logan, Susan K; Sawyers, Charles L
PURPOSE/OBJECTIVE:Metastatic castration-resistant prostate cancer (mCRPC) with low androgen receptor (AR) and without neuroendocrine signaling, termed double-negative prostate cancer (DNPC), is increasingly prevalent in patients treated with AR signaling inhibitors and is in need of new biomarkers and therapeutic targets. METHODS:Candidate genes enriched in DNPC were determined using differential gene expression analysis of discovery and validation cohorts of mCRPC biopsies. Laboratory studies were carried out in human mCRPC organoid cultures, prostate cancer (PCa) cell lines, and mouse xenograft models. Epigenetic studies were carried out in a rapid autopsy cohort. RESULTS:< .0005). Growth inhibition of the human PCa model PC3 by the anti-DKK1 monoclonal antibody DKN-01 depends on the presence of NK cells in a severe combined immunodeficient xenograft mouse model. CONCLUSION/CONCLUSIONS:These results support DKK1 as a contributor to the immunosuppressive tumor microenvironment of DNPC. These data have provided the rationale for a clinical trial targeting DKK1 in mCRPC ( identifier: NCT03837353).
PMID: 33015525
ISSN: 2473-4284
CID: 4626642

Somatic and germline sequencing in genitourinary oncology: genetics for the clinician

Shoag, Jonathan E; Wise, David R; Sharaf, Ravi N; Sternberg, Cora N
PURPOSE OF REVIEW/OBJECTIVE:Next-generation sequencing is becoming more accessible. This review focuses on the clinical application of somatic and germline sequencing to genitourinary oncology. RECENT FINDINGS/RESULTS:Germline variants have been increasingly recognized as contributing to the development of genitourinary malignancies, particularly in patients with advanced disease. A variety of commercial and institutional technologies are in use to detect variants, with newer tools focused on integrating these results into the clinical workflow. SUMMARY/CONCLUSIONS:DNA sequencing is becoming a valuable tool in caring for patients with genitourinary malignancies. Performing both somatic and germline sequencing will likely become standard practice. Interpretation and clinical application of these results can be challenging and often requires multidisciplinary expertise.
PMID: 31158105
ISSN: 1473-6586
CID: 3923352

Phase Ib results of ProSTAR: CPI-1205, EZH2 inhibitor, combined with enzalutamide (E) or abiraterone/prednisone (A/P) in patients with metastatic castration-resistant prostate cancer (mCRPC) [Meeting Abstract]

Taplin, Mary-Ellen; Hussain, Arif; Shah, Satish; Shore, Neal D.; Edenfield, William Jeffery; Sartor, Oliver A.; Nordquist, Luke T.; Agrawal, Manish; Clark, William; Wise, David R.; Oh, William K.; Fleming, Mark T.; Butrynski, James E.; Chatta, Gurkamal S.; Bupathi, Manojkumar; Lebedinsky, Claudia; Senderowicz, Adrian; Li, Jian; Colak, Gozde; Nash, David; Trojer, Patrick; Bradley, William D.; Piel, Jessica; Antonarakis, Emmanuel S.
ISSN: 0008-5472
CID: 4135662

A phase IB open-label, dose escalation and expansion study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of GSK525762 in combination with abiraterone or enzalutamide in metastatic castrate-resistant prostate cancer [Meeting Abstract]

Vaishampayan, U N; Narayan, V; Wise, D; Lang, J M; Lowentritt, B H; Mellado, B; Carles, J; Isabel, Saez M; Abida, W; Taplin, M -E; Azad, A; Wang, K; Barbash, O; Ferron-Brady, G; Fecteau, D; Khaled, A H; Dhar, A; De, Bono J S
Background: Metastatic castrate-resistant prostate cancer (mCRPC) remains an incurable illness as resistance develops after androgen deprivation therapy (ADT) and/or androgen receptor (AR) axis targeted therapies. The bromodomain (BRD) and extraterminal (BET) proteins are critical for transcription. Preclinically, one of these proteins, BRD4, acts in complex with AR to mediate androgen signaling that leads to prostate cell growth and proliferation. GSK525762 is an oral pan-BET inhibitor that suppresses BET dependent activated AR-driven transcription. Combined with androgen production or receptor targeted agents like abiraterone or enzalutamide, GSK525762 may enhance efficacy of or overcome resistance to either agent.
Method(s): This is a Phase IB open-label, dose-escalation study to evaluate the safety and efficacy of oral administration of GSK525762 in combination with either abiraterone plus prednisone (Arm A) or enzalutamide (Arm B) in mCRPC patients whose disease has progressed on prior abiraterone or enzalutamide. Patients must have documented prostate cancer progression as assessed by rising PSA or radiographic progression of soft tissue by PCWG3-modified RECIST 1.1 criteria or bone metastasis. Dose escalation is designed to identify safe doses to move into dose expansion. Dose expansion will explore safety and efficacy in patients who failed in first line (L2 population) or after multiple lines of prior therapy (LX population). Primary objectives include defining the safety, tolerability and clinical activity of GSK525762 when combined with products in Arm A or Arm B. Primary clinical activity endpoint is defined as the response rate of subjects achieving a 50% or more reduction from baseline of PSA at 12 weeks or thereafter. Dose escalation will employ a modified Toxicity Probability Interval (mTPI) design. Dose expansion will use a Bayesian adaptive design, which will calculate posterior probability that utility of the dose is clinically significant at interim futility analysis for each dose level.
Funding(s): GSK Clinical trial information: NCT03150056
ISSN: 1527-7755
CID: 3553952

Cutaneous vulvar metastases in a patient with anal squamous cell carcinoma [Case Report]

Wise, David R; Kim, Brian S; Ferenczi, Katalin; Rosenbach, Misha
Metastatic disease of the skin can be difficult to diagnose, particularly when lesions occur in unusual anatomic locations. We report the case of an 80-year-old woman with a history of anal squamous cell carcinoma (SCC) who developed genital ulcers. Biopsy of the lesions revealed features consistent with metastatic SCC. Cutaneous metastases are an infrequent cause of genital ulcerations, and it is important for physicians to consider this entity when evaluating genital ulcers in patients with prior malignancies.
PMID: 23617081
ISSN: 0011-4162
CID: 2484032

ATF4 regulates MYC-mediated neuroblastoma cell death upon glutamine deprivation

Qing, Guoliang; Li, Bo; Vu, Annette; Skuli, Nicolas; Walton, Zandra E; Liu, Xueyuan; Mayes, Patrick A; Wise, David R; Thompson, Craig B; Maris, John M; Hogarty, Michael D; Simon, M Celeste
Oncogenic Myc alters mitochondrial metabolism, making it dependent on exogenous glutamine (Gln) for cell survival. Accordingly, Gln deprivation selectively induces apoptosis in MYC-overexpressing cells via unknown mechanisms. Using MYCN-amplified neuroblastoma as a model, we identify PUMA, NOXA, and TRB3 as executors of Gln-starved cells. Gln depletion in MYC-transformed cells induces apoptosis through ATF4-dependent, but p53-independent, PUMA and NOXA induction. MYC-transformed cells depend on both glutamate-oxaloacetate transaminase and glutamate dehydrogenase to maintain Gln homeostasis and suppress apoptosis. Consequently, either ATF4 agonists or glutaminolysis inhibitors potently induce apoptosis in vitro and inhibit tumor growth in vivo. These results reveal mechanisms whereby Myc sensitizes cells to apoptosis, and validate ATF4 agonists and inhibitors of Gln metabolism as potential Myc-selective cancer therapeutics.
PMID: 23153536
ISSN: 1878-3686
CID: 2484022

Preparation and characterization of L-[5-11C]-glutamine for metabolic imaging of tumors

Qu, Wenchao; Oya, Shunichi; Lieberman, Brian P; Ploessl, Karl; Wang, Limin; Wise, David R; Divgi, Chaitanya R; Chodosh, Lewis A; Thompson, Craig B; Kung, Hank F
UNLABELLED: Recently, there has been a renewed interest in the study of tumor metabolism above and beyond the Warburg effect. Studies on cancer cell metabolism have provided evidence that tumor-specific activation of signaling pathways, such as the upregulation of the oncogene myc, can regulate glutamine uptake and its metabolism through glutaminolysis to provide the cancer cell with a replacement of energy source. METHODS: We report a convenient procedure to prepare l-[5-(11)C]-glutamine. The tracer was evaluated in 9L and SF188 tumor cells (glioma and astrocytoma cell lines). The biodistribution of l-[5-(11)C]-glutamine in rodent tumor models was investigated by dissection and PET. RESULTS: By reacting (11)C-cyanide ion with protected 4-iodo-2-amino-butanoic ester, the key intermediate was obtained in good yield. After hydrolysis with trifluoroacetic and sulfonic acids, the desired optically pure l-[5-(11)C]-glutamine was obtained (radiochemical yield, 5% at the end of synthesis; radiochemical purity, >95%). Tumor cell uptake studies showed maximum uptake of l-[5-(11)C]-glutamine reached 17.9% and 22.5% per 100 mug of protein, respectively, at 60 min in 9L and SF188 tumor cells. At 30 min after incubation, more than 30% of the activity appeared to be incorporated into cellular protein. Biodistribution in normal mice showed that l-[5-(11)C]-glutamine had significant pancreas uptake (7.37 percentage injected dose per gram at 15 min), most likely due to the exocrine function and high protein turnover within the pancreas. Heart uptake was rapid, and there was 3.34 percentage injected dose per gram remaining at 60 min after injection. Dynamic small-animal PET studies in rats bearing xenografted 9L tumors and in transgenic mice bearing spontaneous mammary gland tumors showed a prominent tumor uptake and retention. CONCLUSION: The data demonstrated that this tracer was favorably taken up in the tumor models. The results suggest that l-[5-(11)C]-glutamine might be useful for probing in vivo tumor metabolism in glutaminolytic tumors.
PMID: 22173839
ISSN: 1535-5667
CID: 2484052

Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of alpha-ketoglutarate to citrate to support cell growth and viability

Wise, David R; Ward, Patrick S; Shay, Jessica E S; Cross, Justin R; Gruber, Joshua J; Sachdeva, Uma M; Platt, Jesse M; DeMatteo, Raymond G; Simon, M Celeste; Thompson, Craig B
Citrate is a critical metabolite required to support both mitochondrial bioenergetics and cytosolic macromolecular synthesis. When cells proliferate under normoxic conditions, glucose provides the acetyl-CoA that condenses with oxaloacetate to support citrate production. Tricarboxylic acid (TCA) cycle anaplerosis is maintained primarily by glutamine. Here we report that some hypoxic cells are able to maintain cell proliferation despite a profound reduction in glucose-dependent citrate production. In these hypoxic cells, glutamine becomes a major source of citrate. Glutamine-derived alpha-ketoglutarate is reductively carboxylated by the NADPH-linked mitochondrial isocitrate dehydrogenase (IDH2) to form isocitrate, which can then be isomerized to citrate. The increased IDH2-dependent carboxylation of glutamine-derived alpha-ketoglutarate in hypoxia is associated with a concomitant increased synthesis of 2-hydroxyglutarate (2HG) in cells with wild-type IDH1 and IDH2. When either starved of glutamine or rendered IDH2-deficient by RNAi, hypoxic cells are unable to proliferate. The reductive carboxylation of glutamine is part of the metabolic reprogramming associated with hypoxia-inducible factor 1 (HIF1), as constitutive activation of HIF1 recapitulates the preferential reductive metabolism of glutamine-derived alpha-ketoglutarate even in normoxic conditions. These data support a role for glutamine carboxylation in maintaining citrate synthesis and cell growth under hypoxic conditions.
PMID: 22106302
ISSN: 1091-6490
CID: 2484062

PET imaging of glutaminolysis in tumors by 18F-(2S,4R)4-fluoroglutamine

Lieberman, Brian P; Ploessl, Karl; Wang, Limin; Qu, Wenchao; Zha, Zhihao; Wise, David R; Chodosh, Lewis A; Belka, George; Thompson, Craig B; Kung, Hank F
UNLABELLED: Changes in gene expression, metabolism, and energy requirements are hallmarks of cancer growth and self-sufficiency. Upregulation of the PI3K/Akt/mTor pathway in tumor cells has been shown to stimulate aerobic glycolysis, which has enabled (18)F-FDG PET tumor imaging. However, of the millions of (18)F-FDG PET scans conducted per year, a significant number of malignant tumors are (18)F-FDG PET-negative. Recent studies suggest that several tumors may use glutamine as the key nutrient for survival. As an alternative metabolic tracer for tumors, (18)F-(2S,4R)4-fluoroglutamine was developed as a PET tracer for mapping glutaminolytic tumors. METHODS: A series of in vitro cell uptake and in vivo animal studies were performed to demonstrate tumor cell addiction to glutamine. Cell uptake studies of this tracer were performed in SF188 and 9L glioblastoma tumor cells. Dynamic small-animal PET studies of (18)F-(2S,4R)4-fluoroglutamine were conducted in 2 animal models: xenografts produced in F344 rats by subcutaneous injection of 9L tumor cells and transgenic mice with M/tomND spontaneous mammary gland tumors. RESULTS: In vitro studies showed that both transformed 9L and SF188 tumor cells displayed a high rate of glutamine uptake (maximum uptake, approximately 16% dose/100 mug of protein). The cell uptake of (18)F-(2S,4R)4-fluoroglutamine by SF188 cells is comparable to that of (3)H-L-glutamine but higher than that of (18)F-FDG. The tumor cell uptake can be selectively blocked. Biodistribution and PET studies showed that (18)F-(2S,4R)4-fluoroglutamine localized in tumors with a higher uptake than in surrounding muscle and liver tissues. Data suggest that certain tumor cells may use glutamine for energy production. CONCLUSION: The results support that (18)F-(2S,4R)4-fluoroglutamine is selectively taken up and trapped by tumor cells. It may be useful as a novel metabolic tracer for tumor imaging.
PMID: 22095958
ISSN: 1535-5667
CID: 2484042

Synthesis of optically pure 4-fluoro-glutamines as potential metabolic imaging agents for tumors

Qu, Wenchao; Zha, Zhihao; Ploessl, Karl; Lieberman, Brian P; Zhu, Lin; Wise, David R; Thompson, Craig B; Kung, Hank F
A versatile synthetic route to prepare all four stereoisomeric 4-fluoro-glutamines was developed by exploiting a Passerini three-component reaction. The skeleton of 4-substituted glutamine derivatives was efficiently constructed. Subsequent four-step reactions, highlighted by a "neutralized" TASF fluorination, provided the desired products with high yields and excellent optical purity. The optically pure fluorine-18 labeled 4-fluoroglutamines were also successfully prepared using either a 18-crown-6/KHCO(3) or K[222]/K(2)CO(3) catalysis system. Preliminary cell uptake and inhibition studies using the 9L tumor cells and SF188(Bcl-xL) tumor cells (a glutamine addicted tumor derived from glioblastoma) provided strong evidence for their potential application in conjunction with positron emission tomography (PET) for in vivo imaging of tumors, which use glutamine as an alternative energy source.
PMID: 21190335
ISSN: 1520-5126
CID: 2484072