William Figg - Academia.edu (original) (raw)

Papers by William Figg

Scientific Reports, 2021

Understanding mechanisms of resistance to abiraterone, one of the primary drugs approved for the ... more Understanding mechanisms of resistance to abiraterone, one of the primary drugs approved for the treatment of castration resistant prostate cancer, remains a priority. The organic anion polypeptide 1B3 (OATP1B3, encoded by SLCO1B3) transporter has been shown to transport androgens into prostate cancer cells. In this study we observed and investigated the mechanism of induction of SLCO1B3 by abiraterone. Prostate cancer cells (22Rv1, LNCaP, and VCAP) were treated with anti-androgens and assessed for SLCO1B3 expression by qPCR analysis. Abiraterone treatment increased SLCO1B3 expression in 22Rv1 cells in vitro and in the 22Rv1 xenograft model in vivo. MicroRNA profiling of abiraterone-treated 22Rv1 cells was performed using a NanoString nCounter miRNA panel followed by miRNA target prediction. TargetScan and miRanda prediction tools identified hsa-miR-579-3p as binding to the 3′-untranslated region (3′UTR) of the SLCO1B3. Using dual luciferase reporter assays, we verified that hsa-miR...

Cancers, 2022

Simple Summary Phase I clinical trials are a cornerstone of pharmaceutical development in oncolog... more Simple Summary Phase I clinical trials are a cornerstone of pharmaceutical development in oncology. Many studies have now attempted to incorporate pharmacogenomics into phase I studies; however, many of these studies have fundamental flaws that that preclude interpretation and application of their findings. Study populations are often small and heterogeneous with multiple disease states, multiple dose levels, and prior therapies. Genetic testing typically includes few variants in candidate genes that do no encapsulate the full range of phenotypic variability in protein function. Moreover, a plurality of these studies do not present scientifically robust clinical or preclinical justification for undertaking pharmacogenomics studies. A significant amount of progress in understanding pharmacogenomic variability has occurred since pharmacogenomics approaches first began appearing in the literature. This progress can be immediately leveraged for the vast majority of Phase I studies. The ...

Cancers, 2021

Prostate cancer has entered into the era of precision medicine with the recent approvals of targe... more Prostate cancer has entered into the era of precision medicine with the recent approvals of targeted therapeutics (olaparib and rucaparib). The presence of germline mutations has important hereditary cancer implications for patients with prostate cancer, and germline testing is increasingly important in cancer screening, risk assessment, and the overall treatment and management of the disease. In this review, we discuss germline variants associated with inherited predisposition, prostate cancer risk and outcomes. We review recommendations for germline testing, available testing platforms, genetic counseling as well as discuss the therapeutic implications of germline variants relevant to prostate cancer treatments. Understanding the role of germline (heritable) mutations that affect prostate cancer biology and risk as well as the subsequent effect of these alterations on potential therapies is critical as the treatment paradigm shifts towards precision medicine. Furthermore, enhancin...

Scientific Reports, 2021

OATP1B3 is expressed de novo in primary prostate cancer tissue and to a greater degree in prostat... more OATP1B3 is expressed de novo in primary prostate cancer tissue and to a greater degree in prostate cancer metastases. Gadoxetate disodium is a substrate of OATP1B3, and its uptake has been shown to correlate with OATP1B3 expression in other cancers. We aimed to evaluate use of gadoxetate disodium to image prostate cancer and to track its utility as a biomarker. A single center open-label non-randomized pilot study recruited men with (1) localized, and (2) metastatic castration resistant prostate cancer (mCRPC). Gadoxetate disodium-enhanced MRI was performed at four timepoints post-injection. The Wilcoxon signed rank test was used to compare MRI contrast enhancement ratio (CER) pre-injection and post-injection. OATP1B3 expression was evaluated via immunohistochemistry (IHC) and a pharmacogenomic analysis of OATP1B3, NCTP and OATP1B1 was conducted. The mCRPC subgroup (n = 9) demonstrated significant enhancement compared to pre-contrast images at 20-, 40- and 60-min timepoints (p < ...

The Oncologist, 2020

The U.S. Food and Drug Administration recently approved two poly-adenosine diphosphate-ribose pol... more The U.S. Food and Drug Administration recently approved two poly-adenosine diphosphate-ribose polymerase (PARP) inhibitors, olaparib and rucaparib, for treatment of biomarker-positive metastatic castrate resistant prostate cancer. The benefits of PARP inhibition have been well characterized in patients who have BRCA1 and BRCA2 mutations in several forms of cancer. BRCA1 and BRCA2 occupy key roles in DNA damage repair, which is comprised of several different pathways with numerous participants. Patients with mutations in other key genes within the DNA damage repair pathway may also respond to treatment with PARP inhibitors, and identification of these alterations could significantly increase the percentage of patients that may benefit from PARP inhibition. This review focuses on the potential for synthetically lethal interactions between PARP inhibitors and non-BRCA DNA damage repair genes.Implications for PracticeThe treatment potential of PARP inhibition has been well characterized...

Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 10, 2018

Purpose Abiraterone acetate (AA) is a standard of care for metastatic castration-resistant prosta... more Purpose Abiraterone acetate (AA) is a standard of care for metastatic castration-resistant prostate cancer (CRPC). Despite a large food effect, AA was administered under fasting conditions in its pivotal trials. We sought to test the hypothesis that low-dose AA (LOW; 250 mg with a low-fat meal) would have comparable activity to standard AA (STD; 1,000 mg fasting) in patients with CRPC. Patients and Methods Patients (n = 72) with progressive CRPC from seven institutions in the United States and Singapore were randomly assigned to STD or LOW. Both arms received prednisone 5 mg twice daily. Prostate-specific antigen (PSA) was assessed monthly, and testosterone/dehydroepiandrosterone sulfate were assessed every 12 weeks with disease burden radiographic assessments. Plasma was collected for drug concentrations. Log change in PSA, as a pharmacodynamic biomarker for efficacy, was the primary end point, using a noninferiority design. Progression-free survival (PFS), PSA response (≥ 50% redu...

Therapeutic advances in medical oncology, 2018

Aided by developments in diagnostics and therapeutics, healthcare is increasingly moving toward p... more Aided by developments in diagnostics and therapeutics, healthcare is increasingly moving toward precision medicine, in which treatment is customized to each individual. We discuss the relevance of precision medicine in prostate cancer, including gene targets, therapeutics and resistance mechanisms. We foresee precision medicine becoming an integral component of prostate cancer management to increase response to therapy and prolong survival.

Pharmacogenomics, 2016

Metabolism and transport play major roles in life-long exposure to endogenous and exogenous carci... more Metabolism and transport play major roles in life-long exposure to endogenous and exogenous carcinogens. We therefore explored associations between polymorphisms in absorption, distribution, metabolism and elimination genes and the risk and prognosis of castration-resistant prostate cancer (CRPC). A total of 634 genotypes were tested in 74 patients using the Affymetrix DMETv1.0 platform. No relation to risk was found. Three SNPs were associated with CRPC prognosis in Caucasians: ABCB11 rs7602171G>A (p = 0.003; n = 30; hazard ratio [HR]: 0.307), GSTP1 rs1799811C>T (p = 0.001; n = 38; HR: 0.254) and SLC5A6 rs1395 (p = 0.004; n = 35; HR: 3.15). Two other polymorphisms among Caucasians were associated with interesting trends: ABCB4 rs2302387C>T (p = 0.039) and ABCC5 rs939339A>G (p = 0.018). This exploratory study is the first to show that polymorphisms in several absorption, distribution, metabolism and elimination genes may be associated with CRPC prognosis.

Translational Cancer Research, 2016

Pharmacogenomics, 2016

The histone deacetylase inhibitor valproic acid (VPA) has been used for many decades in neurology... more The histone deacetylase inhibitor valproic acid (VPA) has been used for many decades in neurology and psychiatry. The more recent introduction of the histone deacetylase inhibitors (HDIs) belinostat, romidepsin and vorinostat for treatment of hematological malignancies indicates the increasing popularity of these agents. Belinostat, romidepsin and vorinostat are metabolized or transported by polymorphic enzymes or drug transporters. Thus, genotype-directed dosing could improve pharmacotherapy by reducing the risk of toxicities or preventing suboptimal treatment. This review provides an overview of clinical studies on the effects of polymorphisms on the pharmacokinetics, efficacy or toxicities of HDIs including belinostat, romidepsin, vorinostat, panobinostat, VPA and a number of novel compounds currently being tested in Phase I and II trials. Although pharmacogenomic studies for HDIs are scarce, available data indicate that therapy with belinostat (UGT1A1), romidepsin (ABCB1), vorin...

Journal of clinical pharmacology, Jan 16, 2016

Precision medicine in oncology is the result of an increasing awareness of patient specific clini... more Precision medicine in oncology is the result of an increasing awareness of patient specific clinical features coupled with the development of genomic-based diagnostics and targeted therapeutics. Companion diagnostics designed for specific drug-target pairs were the first to widely utilize clinically applicable tumor biomarkers (e.g. HER2, EGFR), directing treatment for patients whose tumors exhibit a mutation susceptible to a FDA approved targeted therapy (e.g. trastuzumab, erlotinib). Clinically relevant germline mutations in drug metabolizing enzymes and transporters (e.g. TPMT, DPYD) have been shown to impact drug response, providing rationale for individualized dosing to optimize treatment. The use of multigene expression-based assays to analyze an array of prognostic biomarkers have been shown to help direct treatment decisions, especially in breast cancer (e.g. Oncotype DX). More recently, the use of Next-Generation Sequencing to detect many potential "actionable" ca...

Southern medical journal, 2015

Prostate cancer remains a significant cause of cancer-related deaths in men in the United States.... more Prostate cancer remains a significant cause of cancer-related deaths in men in the United States. Significant advances in the treatment of metastatic castration-resistant prostate cancer have been made in recent years with the arrival of new therapeutic targets and options. The definition of progression of disease must be thought of in the context of clinical symptoms and radiographic evidence rather than as changes in prostate-specific antigen (PSA). Ultimately, the use of PSA criteria alone should not be used to determine the progression of disease; instead, PSA should be evaluated in combination with other clinical data.

Clinical Genitourinary Cancer, 2013

Genetic polymorphisms in DNA repair enzymes (excision repair cross-complementing group 1 [ERCC1] ... more Genetic polymorphisms in DNA repair enzymes (excision repair cross-complementing group 1 [ERCC1] and x-ray cross-complementing group 1 [XRCC1]) may predict treatment outcome and response to platinum-based treatment. Twenty-four patients were enrolled in this single-arm study to assess the association between ERCC1 and XRCC1 gene variants and treatment outcomes with satraplatin in patients with docetaxel-refractory metastatic castration-resistant prostate cancer. Background-We assessed the effect of excision repair cross-complementing group 1 (ERCC1) and x-ray cross-complementing group 1 (XRCC1) gene polymorphisms on treatment outcomes with satraplatin and prednisone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel-based therapy. Patients and Methods-Twenty-four patients were enrolled in this single arm study. The primary objective was to determine if the presence of ERCC1 Asn118Asn (N118N, 500C>T, rs11615) and XRCC1 Arg399Gln (R399Q, 1301G>A, rs25487) genetic variants might be associated with an impact on progression-free survival (PFS); secondary objectives included overall response, survival, and toxicity. Results-After population stratification by race, white patients carrying heterozygous or variant genotypes at the ERCC1 C>T locus had a >3-fold longer median PFS (5.8 vs. 1.8 months; 2P =. 18, adjusted) and 5-fold longer median overall survival (OS) (15.7 vs. 3.2 months; 2P = .010, adjusted) than did patients carrying only wild-type alleles. For the XRCC1 G>A variant, without regard to race, patients carrying the wild-type GG alleles had a longer PFS (9.3 months) than those

Cancer Chemotherapy and Pharmacology, 2014

Purpose-To determine the maximum tolerated dose (MTD) of perifosine (NSC 639966), an alkylphospho... more Purpose-To determine the maximum tolerated dose (MTD) of perifosine (NSC 639966), an alkylphospholipid modulator of signal transduction, using different oral loading and maintenance regimens in an effort to avoid gastrointestinal toxicity while seeking maximal sustained plasma concentrations. Methods-Thirty-one patients with advanced neoplasms were treated with monthly cycles of perifosine loading doses of 300, 600, 900, 1,200 and 1,500 mg (dose levels 1 through 5, respectively) on days 1-2 depending on the actual dose of the initial cycle. For subsequent cycles, perifosine loading doses were reduced to 100, 200, 300, 400 and 1,000 mg at the respective corresponding dose levels. Daily perifosine "maintenance" doses of 50, 100, 150, 200 and 250 mg for levels 1 through 5, respectively, commenced on days 2 or 3 and continued for a total of 21 days. No treatment was given for days 22-27. The pharmacokinetics of perifosine with these schedules was characterized. Results-Dose-limiting diarrhea developed at or above dose level 4. The MTD and recommended phase II dose was dose level 3B, with a loading dose of 900 mg on day 1 divided into two doses of 450 mg administered 6 h apart and a maintenance dose of 150 mg on day 2 through 21. On subsequent cycles, the loading dose was reduced to 300 mg. Non-gastrointestinal toxicities included three episodes of gout or gout-like syndromes observed at doses above the MTD. The median peak plasma concentration of perifosine achieved at the MTD was approximately 8.3 μg/mL. Four patients had stable disease ranging from 167 to 735 days. Conclusions-Perifosine given according to a loading and maintenance schedule can safely sustain concentrations of drug, approaching concentrations achieved in preclinical models with evidence of anti-tumor effect.

Clinical cancer research : an official journal of the American Association for Cancer Research, 2014

Endoglin, an endothelial cell membrane receptor expressed on angiogenic tumor vessels, is essenti... more Endoglin, an endothelial cell membrane receptor expressed on angiogenic tumor vessels, is essential for angiogenesis and upregulated in the setting of VEGF inhibition. TRC105 is an anti-endoglin IgG1 monoclonal antibody that potentiates VEGF inhibitors in preclinical models. This study assessed safety, pharmacokinetics, and antitumor activity of TRC105 in combination with bevacizumab. Patients (n = 38) with advanced solid tumors, Eastern Cooperative Group performance status 0-1, and normal organ function were treated with escalating doses of TRC105 plus bevacizumab until disease progression or unacceptable toxicity using a standard 3 + 3 phase I design. TRC105 and bevacizumab were well tolerated at their recommended single-agent doses (10 mg/kg) when the initial dose of TRC105 was delayed by one week and divided over 2 days to limit the frequency of headache. The concurrent administration of bevacizumab and TRC105 did not otherwise potentiate known toxicities of TRC105 or bevacizuma...

Therapeutics and Clinical Risk Management, 2010

The Oncologist, 2008

Purpose. The slow progress in developing new cancer therapies can be attributed in part to the lo... more Purpose. The slow progress in developing new cancer therapies can be attributed in part to the long time spent in clinical development. To hasten development, new paradigms especially applicable to patients with metastatic disease are needed. Patients and Methods. We present a new method to predict survival using tumor measurement data gathered while a patient with cancer is receiving therapy in a clinical trial. We developed a two-phase equation to estimate the concomitant rates of tumor regression (regression rate constant d) and tumor growth (growth rate constant g). Results. We evaluated the model against serial levels of prostate-specific antigen (PSA) in 112 patients undergoing treatment for prostate cancer. Survival was strongly correlated with the log of the growth rate constant, log(g) (Pearson r = −0.72) but not with the log of the regression rate constants, log(d) (r = −0.218). Values of log(g) exhibited a bimodal distribution. Patients with log(g) values above the median...

Prostate Cancer and Prostatic Diseases, 1999

Prostate cancer is the most common malignancy in men in the US. Both at diagnosis and throughout ... more Prostate cancer is the most common malignancy in men in the US. Both at diagnosis and throughout the disease progression it can metastasize to multiple organs (bone and lymph being the most common). Effusions (either pleural or abdominal) are relatively uncommon, but usually occur as a result of soft tissue lesions. Herein we report on a patient with androgen independent prostate cancer and an elevated PSA with disease con®ned to ascites of the abdomen.

Journal of Urology, 2008

Purpose-Studies have investigated time to testosterone (T) recovery in patients who have undergon... more Purpose-Studies have investigated time to testosterone (T) recovery in patients who have undergone androgen-deprivation therapy (ADT)-usually by measuring androgens every 3 months-with varying results. This represents the largest study utilizing monthly measurements of both T and dihydroxytestosterone (DHT) to evaluate the kinetics of androgen recovery following limited ADT. Materials and Methods-Monthly serum androgen levels were analyzed following two 6-month cycles of gonadotropin-releasing hormone agonist (GnRH-A) therapy as part of a randomized placebo-controlled study evaluating the role of thalidomide in delaying time to prostate-specific androgen progression. Results-By the Kaplan-Meier method, the median time to T normalization in cycle 1 was 15.4 weeks versus 18.3 weeks in cycle 2, with similar recovery times of DHT. Neither on-study PSA,

Journal of Urology, 2010

Purpose-High-dose ketoconazole and docetaxel have shown activity as single agents against castrat... more Purpose-High-dose ketoconazole and docetaxel have shown activity as single agents against castration-resistant prostate cancer (CRPC). The goal of this phase I study was to determine the maximum tolerated doses, side effects, and pharmacokinetic interaction of coadministered docetaxel and ketoconazole. Experimental Design-Patients with metastatic CRPC received weekly docetaxel for 3 of every 4 weeks, plus daily ketoconazole. Pharmacokinetic studies were performed on day 1 (docetaxel alone) and day 16 (after ketoconazole). Results-The study enrolled 42 patients at 9 different dose levels. The combination regimens investigated included docetaxel weekly for three weeks out of four escalating from 5 to 43 mg/m 2 , with starting doses of ketoconazole of 600, 800, or 1200 mg/day. Declines in prostate-specific antigen of ≥ 50% were seen in 62% of patients. Of 25 patients with soft tissue disease, 7 (28%) had partial response. Median overall survival was 22.8 months, and was significantly greater in docetaxel-naïve patients than in patients pretreated with docetaxel (36.8 vs. 10.3 months; P = 0.0001). The most frequently observed adverse events were anemia, edema, fatigue, diarrhea, nausea, sensory neuropathy, and elevated liver function tests. The fractional change in docetaxel clearance correlated significantly with ketoconazole exposure (P < 0.01). Concomitant ketoconazole increased docetaxel exposure 2.6-fold with 1200 mg/day, 1.6-fold with 800 mg/day, and 1.3-to 1.5-fold with 600 mg/day. Conclusions-Results suggest that the combination of weekly docetaxel and ketoconazole has significant antitumor activity in CRPC with manageable toxicities. The extremely long survival in the docetaxel-naïve cohort (36.8 months) warrants additional larger trials of docetaxel with ketoconazole or possibly CYP17A1 inhibitors such as abiraterone.

Scientific Reports, 2021

Understanding mechanisms of resistance to abiraterone, one of the primary drugs approved for the ... more Understanding mechanisms of resistance to abiraterone, one of the primary drugs approved for the treatment of castration resistant prostate cancer, remains a priority. The organic anion polypeptide 1B3 (OATP1B3, encoded by SLCO1B3) transporter has been shown to transport androgens into prostate cancer cells. In this study we observed and investigated the mechanism of induction of SLCO1B3 by abiraterone. Prostate cancer cells (22Rv1, LNCaP, and VCAP) were treated with anti-androgens and assessed for SLCO1B3 expression by qPCR analysis. Abiraterone treatment increased SLCO1B3 expression in 22Rv1 cells in vitro and in the 22Rv1 xenograft model in vivo. MicroRNA profiling of abiraterone-treated 22Rv1 cells was performed using a NanoString nCounter miRNA panel followed by miRNA target prediction. TargetScan and miRanda prediction tools identified hsa-miR-579-3p as binding to the 3′-untranslated region (3′UTR) of the SLCO1B3. Using dual luciferase reporter assays, we verified that hsa-miR...

Cancers, 2022

Simple Summary Phase I clinical trials are a cornerstone of pharmaceutical development in oncolog... more Simple Summary Phase I clinical trials are a cornerstone of pharmaceutical development in oncology. Many studies have now attempted to incorporate pharmacogenomics into phase I studies; however, many of these studies have fundamental flaws that that preclude interpretation and application of their findings. Study populations are often small and heterogeneous with multiple disease states, multiple dose levels, and prior therapies. Genetic testing typically includes few variants in candidate genes that do no encapsulate the full range of phenotypic variability in protein function. Moreover, a plurality of these studies do not present scientifically robust clinical or preclinical justification for undertaking pharmacogenomics studies. A significant amount of progress in understanding pharmacogenomic variability has occurred since pharmacogenomics approaches first began appearing in the literature. This progress can be immediately leveraged for the vast majority of Phase I studies. The ...

Cancers, 2021

Prostate cancer has entered into the era of precision medicine with the recent approvals of targe... more Prostate cancer has entered into the era of precision medicine with the recent approvals of targeted therapeutics (olaparib and rucaparib). The presence of germline mutations has important hereditary cancer implications for patients with prostate cancer, and germline testing is increasingly important in cancer screening, risk assessment, and the overall treatment and management of the disease. In this review, we discuss germline variants associated with inherited predisposition, prostate cancer risk and outcomes. We review recommendations for germline testing, available testing platforms, genetic counseling as well as discuss the therapeutic implications of germline variants relevant to prostate cancer treatments. Understanding the role of germline (heritable) mutations that affect prostate cancer biology and risk as well as the subsequent effect of these alterations on potential therapies is critical as the treatment paradigm shifts towards precision medicine. Furthermore, enhancin...

Scientific Reports, 2021

OATP1B3 is expressed de novo in primary prostate cancer tissue and to a greater degree in prostat... more OATP1B3 is expressed de novo in primary prostate cancer tissue and to a greater degree in prostate cancer metastases. Gadoxetate disodium is a substrate of OATP1B3, and its uptake has been shown to correlate with OATP1B3 expression in other cancers. We aimed to evaluate use of gadoxetate disodium to image prostate cancer and to track its utility as a biomarker. A single center open-label non-randomized pilot study recruited men with (1) localized, and (2) metastatic castration resistant prostate cancer (mCRPC). Gadoxetate disodium-enhanced MRI was performed at four timepoints post-injection. The Wilcoxon signed rank test was used to compare MRI contrast enhancement ratio (CER) pre-injection and post-injection. OATP1B3 expression was evaluated via immunohistochemistry (IHC) and a pharmacogenomic analysis of OATP1B3, NCTP and OATP1B1 was conducted. The mCRPC subgroup (n = 9) demonstrated significant enhancement compared to pre-contrast images at 20-, 40- and 60-min timepoints (p < ...

The Oncologist, 2020

The U.S. Food and Drug Administration recently approved two poly-adenosine diphosphate-ribose pol... more The U.S. Food and Drug Administration recently approved two poly-adenosine diphosphate-ribose polymerase (PARP) inhibitors, olaparib and rucaparib, for treatment of biomarker-positive metastatic castrate resistant prostate cancer. The benefits of PARP inhibition have been well characterized in patients who have BRCA1 and BRCA2 mutations in several forms of cancer. BRCA1 and BRCA2 occupy key roles in DNA damage repair, which is comprised of several different pathways with numerous participants. Patients with mutations in other key genes within the DNA damage repair pathway may also respond to treatment with PARP inhibitors, and identification of these alterations could significantly increase the percentage of patients that may benefit from PARP inhibition. This review focuses on the potential for synthetically lethal interactions between PARP inhibitors and non-BRCA DNA damage repair genes.Implications for PracticeThe treatment potential of PARP inhibition has been well characterized...

Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 10, 2018

Purpose Abiraterone acetate (AA) is a standard of care for metastatic castration-resistant prosta... more Purpose Abiraterone acetate (AA) is a standard of care for metastatic castration-resistant prostate cancer (CRPC). Despite a large food effect, AA was administered under fasting conditions in its pivotal trials. We sought to test the hypothesis that low-dose AA (LOW; 250 mg with a low-fat meal) would have comparable activity to standard AA (STD; 1,000 mg fasting) in patients with CRPC. Patients and Methods Patients (n = 72) with progressive CRPC from seven institutions in the United States and Singapore were randomly assigned to STD or LOW. Both arms received prednisone 5 mg twice daily. Prostate-specific antigen (PSA) was assessed monthly, and testosterone/dehydroepiandrosterone sulfate were assessed every 12 weeks with disease burden radiographic assessments. Plasma was collected for drug concentrations. Log change in PSA, as a pharmacodynamic biomarker for efficacy, was the primary end point, using a noninferiority design. Progression-free survival (PFS), PSA response (≥ 50% redu...

Therapeutic advances in medical oncology, 2018

Aided by developments in diagnostics and therapeutics, healthcare is increasingly moving toward p... more Aided by developments in diagnostics and therapeutics, healthcare is increasingly moving toward precision medicine, in which treatment is customized to each individual. We discuss the relevance of precision medicine in prostate cancer, including gene targets, therapeutics and resistance mechanisms. We foresee precision medicine becoming an integral component of prostate cancer management to increase response to therapy and prolong survival.

Pharmacogenomics, 2016

Metabolism and transport play major roles in life-long exposure to endogenous and exogenous carci... more Metabolism and transport play major roles in life-long exposure to endogenous and exogenous carcinogens. We therefore explored associations between polymorphisms in absorption, distribution, metabolism and elimination genes and the risk and prognosis of castration-resistant prostate cancer (CRPC). A total of 634 genotypes were tested in 74 patients using the Affymetrix DMETv1.0 platform. No relation to risk was found. Three SNPs were associated with CRPC prognosis in Caucasians: ABCB11 rs7602171G>A (p = 0.003; n = 30; hazard ratio [HR]: 0.307), GSTP1 rs1799811C>T (p = 0.001; n = 38; HR: 0.254) and SLC5A6 rs1395 (p = 0.004; n = 35; HR: 3.15). Two other polymorphisms among Caucasians were associated with interesting trends: ABCB4 rs2302387C>T (p = 0.039) and ABCC5 rs939339A>G (p = 0.018). This exploratory study is the first to show that polymorphisms in several absorption, distribution, metabolism and elimination genes may be associated with CRPC prognosis.

Translational Cancer Research, 2016

Pharmacogenomics, 2016

The histone deacetylase inhibitor valproic acid (VPA) has been used for many decades in neurology... more The histone deacetylase inhibitor valproic acid (VPA) has been used for many decades in neurology and psychiatry. The more recent introduction of the histone deacetylase inhibitors (HDIs) belinostat, romidepsin and vorinostat for treatment of hematological malignancies indicates the increasing popularity of these agents. Belinostat, romidepsin and vorinostat are metabolized or transported by polymorphic enzymes or drug transporters. Thus, genotype-directed dosing could improve pharmacotherapy by reducing the risk of toxicities or preventing suboptimal treatment. This review provides an overview of clinical studies on the effects of polymorphisms on the pharmacokinetics, efficacy or toxicities of HDIs including belinostat, romidepsin, vorinostat, panobinostat, VPA and a number of novel compounds currently being tested in Phase I and II trials. Although pharmacogenomic studies for HDIs are scarce, available data indicate that therapy with belinostat (UGT1A1), romidepsin (ABCB1), vorin...

Journal of clinical pharmacology, Jan 16, 2016

Precision medicine in oncology is the result of an increasing awareness of patient specific clini... more Precision medicine in oncology is the result of an increasing awareness of patient specific clinical features coupled with the development of genomic-based diagnostics and targeted therapeutics. Companion diagnostics designed for specific drug-target pairs were the first to widely utilize clinically applicable tumor biomarkers (e.g. HER2, EGFR), directing treatment for patients whose tumors exhibit a mutation susceptible to a FDA approved targeted therapy (e.g. trastuzumab, erlotinib). Clinically relevant germline mutations in drug metabolizing enzymes and transporters (e.g. TPMT, DPYD) have been shown to impact drug response, providing rationale for individualized dosing to optimize treatment. The use of multigene expression-based assays to analyze an array of prognostic biomarkers have been shown to help direct treatment decisions, especially in breast cancer (e.g. Oncotype DX). More recently, the use of Next-Generation Sequencing to detect many potential "actionable" ca...

Southern medical journal, 2015

Prostate cancer remains a significant cause of cancer-related deaths in men in the United States.... more Prostate cancer remains a significant cause of cancer-related deaths in men in the United States. Significant advances in the treatment of metastatic castration-resistant prostate cancer have been made in recent years with the arrival of new therapeutic targets and options. The definition of progression of disease must be thought of in the context of clinical symptoms and radiographic evidence rather than as changes in prostate-specific antigen (PSA). Ultimately, the use of PSA criteria alone should not be used to determine the progression of disease; instead, PSA should be evaluated in combination with other clinical data.

Clinical Genitourinary Cancer, 2013

Genetic polymorphisms in DNA repair enzymes (excision repair cross-complementing group 1 [ERCC1] ... more Genetic polymorphisms in DNA repair enzymes (excision repair cross-complementing group 1 [ERCC1] and x-ray cross-complementing group 1 [XRCC1]) may predict treatment outcome and response to platinum-based treatment. Twenty-four patients were enrolled in this single-arm study to assess the association between ERCC1 and XRCC1 gene variants and treatment outcomes with satraplatin in patients with docetaxel-refractory metastatic castration-resistant prostate cancer. Background-We assessed the effect of excision repair cross-complementing group 1 (ERCC1) and x-ray cross-complementing group 1 (XRCC1) gene polymorphisms on treatment outcomes with satraplatin and prednisone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel-based therapy. Patients and Methods-Twenty-four patients were enrolled in this single arm study. The primary objective was to determine if the presence of ERCC1 Asn118Asn (N118N, 500C>T, rs11615) and XRCC1 Arg399Gln (R399Q, 1301G>A, rs25487) genetic variants might be associated with an impact on progression-free survival (PFS); secondary objectives included overall response, survival, and toxicity. Results-After population stratification by race, white patients carrying heterozygous or variant genotypes at the ERCC1 C>T locus had a >3-fold longer median PFS (5.8 vs. 1.8 months; 2P =. 18, adjusted) and 5-fold longer median overall survival (OS) (15.7 vs. 3.2 months; 2P = .010, adjusted) than did patients carrying only wild-type alleles. For the XRCC1 G>A variant, without regard to race, patients carrying the wild-type GG alleles had a longer PFS (9.3 months) than those

Cancer Chemotherapy and Pharmacology, 2014

Purpose-To determine the maximum tolerated dose (MTD) of perifosine (NSC 639966), an alkylphospho... more Purpose-To determine the maximum tolerated dose (MTD) of perifosine (NSC 639966), an alkylphospholipid modulator of signal transduction, using different oral loading and maintenance regimens in an effort to avoid gastrointestinal toxicity while seeking maximal sustained plasma concentrations. Methods-Thirty-one patients with advanced neoplasms were treated with monthly cycles of perifosine loading doses of 300, 600, 900, 1,200 and 1,500 mg (dose levels 1 through 5, respectively) on days 1-2 depending on the actual dose of the initial cycle. For subsequent cycles, perifosine loading doses were reduced to 100, 200, 300, 400 and 1,000 mg at the respective corresponding dose levels. Daily perifosine "maintenance" doses of 50, 100, 150, 200 and 250 mg for levels 1 through 5, respectively, commenced on days 2 or 3 and continued for a total of 21 days. No treatment was given for days 22-27. The pharmacokinetics of perifosine with these schedules was characterized. Results-Dose-limiting diarrhea developed at or above dose level 4. The MTD and recommended phase II dose was dose level 3B, with a loading dose of 900 mg on day 1 divided into two doses of 450 mg administered 6 h apart and a maintenance dose of 150 mg on day 2 through 21. On subsequent cycles, the loading dose was reduced to 300 mg. Non-gastrointestinal toxicities included three episodes of gout or gout-like syndromes observed at doses above the MTD. The median peak plasma concentration of perifosine achieved at the MTD was approximately 8.3 μg/mL. Four patients had stable disease ranging from 167 to 735 days. Conclusions-Perifosine given according to a loading and maintenance schedule can safely sustain concentrations of drug, approaching concentrations achieved in preclinical models with evidence of anti-tumor effect.

Clinical cancer research : an official journal of the American Association for Cancer Research, 2014

Endoglin, an endothelial cell membrane receptor expressed on angiogenic tumor vessels, is essenti... more Endoglin, an endothelial cell membrane receptor expressed on angiogenic tumor vessels, is essential for angiogenesis and upregulated in the setting of VEGF inhibition. TRC105 is an anti-endoglin IgG1 monoclonal antibody that potentiates VEGF inhibitors in preclinical models. This study assessed safety, pharmacokinetics, and antitumor activity of TRC105 in combination with bevacizumab. Patients (n = 38) with advanced solid tumors, Eastern Cooperative Group performance status 0-1, and normal organ function were treated with escalating doses of TRC105 plus bevacizumab until disease progression or unacceptable toxicity using a standard 3 + 3 phase I design. TRC105 and bevacizumab were well tolerated at their recommended single-agent doses (10 mg/kg) when the initial dose of TRC105 was delayed by one week and divided over 2 days to limit the frequency of headache. The concurrent administration of bevacizumab and TRC105 did not otherwise potentiate known toxicities of TRC105 or bevacizuma...

Therapeutics and Clinical Risk Management, 2010

The Oncologist, 2008

Purpose. The slow progress in developing new cancer therapies can be attributed in part to the lo... more Purpose. The slow progress in developing new cancer therapies can be attributed in part to the long time spent in clinical development. To hasten development, new paradigms especially applicable to patients with metastatic disease are needed. Patients and Methods. We present a new method to predict survival using tumor measurement data gathered while a patient with cancer is receiving therapy in a clinical trial. We developed a two-phase equation to estimate the concomitant rates of tumor regression (regression rate constant d) and tumor growth (growth rate constant g). Results. We evaluated the model against serial levels of prostate-specific antigen (PSA) in 112 patients undergoing treatment for prostate cancer. Survival was strongly correlated with the log of the growth rate constant, log(g) (Pearson r = −0.72) but not with the log of the regression rate constants, log(d) (r = −0.218). Values of log(g) exhibited a bimodal distribution. Patients with log(g) values above the median...

Prostate Cancer and Prostatic Diseases, 1999

Prostate cancer is the most common malignancy in men in the US. Both at diagnosis and throughout ... more Prostate cancer is the most common malignancy in men in the US. Both at diagnosis and throughout the disease progression it can metastasize to multiple organs (bone and lymph being the most common). Effusions (either pleural or abdominal) are relatively uncommon, but usually occur as a result of soft tissue lesions. Herein we report on a patient with androgen independent prostate cancer and an elevated PSA with disease con®ned to ascites of the abdomen.

Journal of Urology, 2008

Purpose-Studies have investigated time to testosterone (T) recovery in patients who have undergon... more Purpose-Studies have investigated time to testosterone (T) recovery in patients who have undergone androgen-deprivation therapy (ADT)-usually by measuring androgens every 3 months-with varying results. This represents the largest study utilizing monthly measurements of both T and dihydroxytestosterone (DHT) to evaluate the kinetics of androgen recovery following limited ADT. Materials and Methods-Monthly serum androgen levels were analyzed following two 6-month cycles of gonadotropin-releasing hormone agonist (GnRH-A) therapy as part of a randomized placebo-controlled study evaluating the role of thalidomide in delaying time to prostate-specific androgen progression. Results-By the Kaplan-Meier method, the median time to T normalization in cycle 1 was 15.4 weeks versus 18.3 weeks in cycle 2, with similar recovery times of DHT. Neither on-study PSA,

Journal of Urology, 2010

Purpose-High-dose ketoconazole and docetaxel have shown activity as single agents against castrat... more Purpose-High-dose ketoconazole and docetaxel have shown activity as single agents against castration-resistant prostate cancer (CRPC). The goal of this phase I study was to determine the maximum tolerated doses, side effects, and pharmacokinetic interaction of coadministered docetaxel and ketoconazole. Experimental Design-Patients with metastatic CRPC received weekly docetaxel for 3 of every 4 weeks, plus daily ketoconazole. Pharmacokinetic studies were performed on day 1 (docetaxel alone) and day 16 (after ketoconazole). Results-The study enrolled 42 patients at 9 different dose levels. The combination regimens investigated included docetaxel weekly for three weeks out of four escalating from 5 to 43 mg/m 2 , with starting doses of ketoconazole of 600, 800, or 1200 mg/day. Declines in prostate-specific antigen of ≥ 50% were seen in 62% of patients. Of 25 patients with soft tissue disease, 7 (28%) had partial response. Median overall survival was 22.8 months, and was significantly greater in docetaxel-naïve patients than in patients pretreated with docetaxel (36.8 vs. 10.3 months; P = 0.0001). The most frequently observed adverse events were anemia, edema, fatigue, diarrhea, nausea, sensory neuropathy, and elevated liver function tests. The fractional change in docetaxel clearance correlated significantly with ketoconazole exposure (P < 0.01). Concomitant ketoconazole increased docetaxel exposure 2.6-fold with 1200 mg/day, 1.6-fold with 800 mg/day, and 1.3-to 1.5-fold with 600 mg/day. Conclusions-Results suggest that the combination of weekly docetaxel and ketoconazole has significant antitumor activity in CRPC with manageable toxicities. The extremely long survival in the docetaxel-naïve cohort (36.8 months) warrants additional larger trials of docetaxel with ketoconazole or possibly CYP17A1 inhibitors such as abiraterone.