Early Stage Prostate Cancer Research Articles

CRISPR-Cas12a powered multifunctional DNA nanodumbbell lock biosensor for multiple molecular detection

Detection of multiple biomarkers for accurate diagnosis of disease is highly desirable but remains challenging. Here, we developed a versatile diagnostic biosensor (SMARTLOCK) through the unique combination of DNA tetrahedron, nonlinear HCR and CRISPR-Cas12a system for simultaneous detection of multiple nucleic acids, small molecules, proteins and different types of combinations. Two DNA tetrahedrons are assembled into a functional dumbbell lock, which was unlocked by the target molecules, thereby triggering a two-stage signal amplification of nonlinear HCR and CRISPR-Cas12a to generate powerful fluorescence signals. The capability of multi-target simultaneous detection of SMARTLOCK is demonstrated in the detection of miR-141, miR-375, miR-21, ATP, cortisol, insulin and their combinations. SMARTLOCK could selectively (specificity = 93.3%) and sensitively (sensitivity = 90%) distinguish early-stage prostate cancer (PCa) patients (n = 10) from healthy donors (n = 30). Measurement of two PCa-related RNAs (miR-141 and miR-375) shows the potential of SMARTLOCK to be a highly accurate and low-cost tool for the screening, diagnosis and prognosis of various diseases.

Assessing the Effect of Cancer Diagnosis on Beliefs about Comorbid Diabetes

ObjectivesIncreasingly, patients diagnosed with cancer also live with chronic comorbidities, and it is important to understand the impact of a new cancer diagnosis on perceptions about preexisting conditions. This study assessed the effect of cancer diagnosis on beliefs about comorbid diabetes mellitus and assessed changes in beliefs about cancer and diabetes over time. Data SourcesWe recruited 75 patients with type 2 diabetes who were newly diagnosed with early-stage breast, prostate, lung, or colorectal cancer and 104 age-, sex-, and hemoglobin A1c−matched controls. Participants completed the Brief Illness Perception Questionnaire four times over 12 months. The authors examined within-patient and between-group differences in cancer and diabetes beliefs at baseline and over time. ResultsOverall, diabetes beliefs did not differ between cancer patients and controls at baseline. Cancer patients’ beliefs about diabetes varied significantly over time; they reported less concern about cancer, less emotional effect, and greater cancer knowledge over time. Participants without cancer were significantly more likely to report that diabetes affected their life across all time points, though this effect did not persist after adjustment for sociodemographic variables. ConclusionWhile all patients’ diabetes beliefs were similar at baseline and 12 months, cancer patients’ beliefs about both illnesses fluctuated during the months following cancer diagnosis. Implications for Nursing PracticeOncology nurses can play a key role in recognizing the effects of cancer diagnosis on beliefs about comorbid conditions and fluctuations in these beliefs during treatment. Assessing and communicating patient beliefs between oncology and other practitioners could produce more effective care plans based on patients’ current outlook on their health.

Abstract 2877: Profiling of myeloid-derived suppressor cells in Pten-deficient in prostate cancer progression

Abstract Myeloid-derived suppressor cells (MDSCs) are a heterogenous population of immature immune cells that expand during cancer and can induce potent immune suppression. These cells play critical roles in supporting tumor growth and progression and their induction has been associated with the inactivation of PTEN. To date, few therapies targeting these cells are available which is partly due to their increasingly complex nature and context-dependent functions. Moreover, there is no clear definition to identify these cells. Enhancing our understanding of this cell population will aid in developing more effective cancer therapies. Here, we used gene expression profiling, flow cytometry, and quantitative immunohistochemistry to characterize tumor-infiltrating and circulating MDSCs in prostate carcinogenesis and progression in transgenic mouse models of prostate cancer driven by the conditional inactivation of Pten and Trp53. Transcriptomic profiling revealed enrichment of various myeloid-derived cell signatures in the early stages of prostate cancer including MDSCs, macrophages, and neutrophils. Flow cytometric analysis confirmed the increased infiltration of CD11b+/Ly6G+ (polymorphonuclear MDSCs (pMDSCs)) and CD11b+/Ly6C+ (monocytic MDSCs (mMDSCs)) cells in prostate tumors. The temporal dynamics of tumor-infiltrating myeloid cells were further profiled and showed that pMDSC and mMDSC abundances were 1.6 and 5.7-fold higher, respectively, in older mice with late-stage locally invasive adenocarcinomas (AdCa) compared to younger mice with early-stage prostatic intraepithelial neoplasia (PIN). In both instances, pMDSCs comprised most of the leukocyte infiltrate, however, mMDSCs tended to be positively correlated with tumor burden in AdCa but not PIN. In peripheral blood, CD44+/CD62L+ immature neutrophils were associated with high tumor burden in aged mice. Treatments targeting the androgen receptor (AR) signaling further exacerbated pMDSC infiltration in tumors and was associated with resistance to second androgen receptor-targeted agent (ARTA) therapy in a model of castration resistant prostate cancer. Our findings indicate that MDSCs are a prominent population in Pten-null prostate cancer and are implicated with resistance to prostate cancer treatment. MDSCs constitute a potentially targetable population and these models serve as viable platforms to further investigate their biological activity and further evaluate novel MDSC-directed therapies. Citation Format: Marco A. De Velasco, Yurie Kura, Noriko Sako, Naomi Ando, Kazuko Sakai, Eri Banno, Shogo Adomi, Mitsuhisa Nishimoto, Takafumi Minami, Yasunori Mori, Kazutoshi Fujita, Masahiro Nozawa Nozawa, Kazuhiro Yoshimura, Kazuto Nishio, Hirotsugu Uemura. Profiling of myeloid-derived suppressor cells in Pten-deficient in prostate cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2877.

Abstract 1638: Validation of a novel pan-Ras inhibitor, ADT-007, against lethal variants of prostate cancer

Abstract Metastatic prostate cancer is the second leading cause of cancer deaths in US men. Most early-stage PCa are dependent on overexpression of the androgen receptor (AR) and are therefore sensitive to androgen deprivation therapies. However, eventual resistance to standard medical castration and secondary chemotherapies including next-generation AR-targeting agents like abiraterone or enzalutamide and taxanes (Docetaxel or cabazitaxel) is nearly universal. Further, neuroendocrine PCa or NEPC, a poorly differentiated aggressive variant of PCa that lacks AR expression, and the presence of cancer stem-like cells with self-renewal and differentiation (epithelial to mesenchymal trans-differentiation or EMT) capacities significantly contribute to the development of clinically most aggressive and lethal variants of PCa. Endogenous Ras/ERK/MAPK signaling is known to drive prostate tumor formation, cancer progression, cell migration, and the acquisition of mesenchymal phenotype (EMT) in metastatic prostate cancers. Ras family members are responsible for modulating the function of most of the receptors upregulated in advanced PCa, including AR, so that AR can be functional even in the absence of physiologic levels of androgen. Previous studies have reported that the NSAID, sulindac, inhibits Ras-induced transformation and directly binds Ras. In this study, we show that a non-COX inhibitory sulindac derivative, ADT-007, is a potent drug candidate against lethal PCa. First, we performed single-cell RNA sequencing as a biomarker-based drug screen and showed that chemo-resistant, drug-tolerant, stem-cell-like PCa cell clusters had high expression of Ras genes, indicating that the Ras inhibitor, ADT-007, may be effective in targeting these aggressive subclones. Next, using several cell-based assays on a large panel of lethal PCa cell lines representing metastatic castration-resistant PCa (mCRPC), NEPC as well as African American ancestry, we showed that ADT-007 is highly effective as a single-agent and in combination with taxanes. Combination index values were <0.7, and BLISS scores were >10, indicating very high synergy. Finally, using pre-vs-post-treatment bulk RNAseq, we demonstrated that ADT-007 is indeed effective in downregulating KRas and NRas in a dose-dependent manner. In addition, ingenuity pathway analysis (IPA) predicted significant downregulation of cell cycle, DNA replication, CCND1, AR, and the lncRNA ELDR, and upregulation of autophagy and interferon pathway genes, and the microRNA miR-96. Finally, using PCa patient datasets, we showed that ADT-007 is potentially capable of reversing the expression of several genes associated with biochemical recurrence. Thus, our results show that ADT-007 is a novel drug candidate that circumvents subclonal aggressiveness, drug resistance, and stemness in lethal PCa through simultaneous inhibition of multiple oncogenic factors/pathways. Citation Format: Taraswi Mitra Ghosh, Adam B. Keeton, Xi Chen, Salsabil Ahmed, Razan S. Waliagha, Gary A. Piazza, Amit K. Mitra. Validation of a novel pan-Ras inhibitor, ADT-007, against lethal variants of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1638.

Abstract 4335: Repurposing metformin in early-stage high risk prostate cancer to avoid ADT-induced cardiovascular toxicity

Abstract Prostate cancer is the second most common cause of cancer-related deaths in American men. About 20-40% of patients with localized castration-sensitive prostate cancer (CSPC) eventually progress, requiring androgen deprivation therapy (ADT). However ADT inevitably fails, giving rise to castration-resistant prostate cancer (CRPC), which is incurable and fatal. A significant fraction of patients undergoing ADT die of treatment-accelerated cardiovascular disease. Pre-existing metabolic dysfunction has been implicated in PC disease incidence, higher rates of prostatectomy failure, and accelerated progression to CRPC. Thus, there is an unmet need to counter the adverse sequelae of ADT through alternative CSPC treatments that do not exacerbate metabolic syndrome but prevent PC progression. Few studies have evaluated whether targeting the metabolic dysfunction associated with early-stage PC can prevent progression and thus the need for ADT. In a recent clinical trial spearheaded by Dr. Bilusic, metformin, an affordable and well-tolerated insulin-sensitizing diabetes drug, has recently shown promise as monotherapy in biologically-recurrent CSPC, preventing PSA rise in about 40% of high-risk patients. To identify the molecular mechanisms and biomarkers of positive response to metformin in PC patients, we performed preliminary cytokine profiling of responder vs non-responder patient sera. We found that mitigation of inflammatory factors implicated in cardiovascular disease as well as markers of pro-apoptotic response are associated with positive metformin response. We also found that metformin responders exhibited pre-treatment cytokine signatures associated with inflammatory metabolic diseases, including diabetes and hyperinsulinemia, which are conditions known to benefit from metformin treatment. We have been able to model the variability of metformin treatment response in two well-characterized CSPC cell lines, LNCaP (highly responsive) and LAPC4 (minimally responsive). Metformin induced cell death in LNCaP but not in LAPC4, which possesses mutant p53 and high Bcl-2 levels. LAPC4 instead showed markers of senescence, which is associated with an inflammatory phenotype. Metformin also elevated levels of damaging high-potency (short-lived) ROS in LNCaP to a greater extent than in LAPC4. LAPC4 instead exhibited elevated levels of hydrogen peroxide upon metformin treatment, a ROS associated with inflammation. Thus the cell models show congruence with factors of positive response seen in patients. Our findings shed light on the potential mechanism of positive response to metformin in CSPC patients, and lay the groundwork for further investigation, while insight into biomarkers predicting positive response could be immediately useful in the clinic. Citation Format: Philip Gregory, Beatriz Mateo-Victoriano, Ling Zhang, Cassie Due, Marijo Bilusic, Priyamvada Rai. Repurposing metformin in early-stage high risk prostate cancer to avoid ADT-induced cardiovascular toxicity. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4335.

Abstract 5261: Prostate specific sustained anti androgen delivery to delay early stage prostate cancer progression

Abstract Prostate cancer is the most common cancer in men. Commensurate with risk, current approaches to localized prostate cancer include prostatectomy, prostate radiation with or without radiation therapy or active surveillance. Recent data suggest that systemic anti-androgen therapy with enzalutamide reduced the risk of prostate cancer progression in men on active surveillance but was associated with considerable side effects. We developed a novel polymer-based drug delivery method to provide sustained localized drug administration of anti-androgens selectively to the prostate. In vitro and in vivo mouse and canine studies show that this drug eluting implant delivers sustained high prostate to plasma therapeutic anti-androgen levels for an anticipated range of 2 years while preventing accumulation of anti-androgens in the liver, lungs, heart and brain. We performed a proof of concept study in a canine prostate model implanting an 15mm x 1mm bicalutamide eluting implant into each lobe of the prostate. Bicalutamide levels in the prostate measured near the implant at 6 months were 3250 ± 1622 ng/g, n = 3 compared to 3809 ± 638 ng/g, n = 3 to those achieved at steady-state oral administration. Plasma and other off target levels were over 1000-fold lower in the implant cohort compared to oral administration: Plasma: 5.9 ± 0.2 ng/ml, liver: 11.3 ±4.3 ng/g, and brain: 5.4 ±0.8 ng/g versus plasma: 18170 ± 3820 ng/ml, liver: 35407 ±8510 ng/g, and brain: 8870 ±1797 ng/g. The implants were well tolerated without local toxicity and imaged easily with ultrasound. The design characteristics of the implant facilitates minimally invasive surgical implantation under standard image guidance and withstands the concomitant use of prostate radiation. This novel technology warrants future clinical exploration of prostate specific anti-androgen therapy for (neo)adjuvant therapy or in active surveillance. Tissue Bicalutamide oral (2m)(ng/g) Bicalutamide implant (6m)(ng/g) Plasma 18,170 (3820) 5.9 (0.2) Prostate 3,809 (638) 3,250 (1622) Liver 35,407 (8510) 11.3 (4.3) Cerebrum 8,870 (1797) 5.4 (0.8) Cerebellum 8,737 (1550) 6.2 (1.3) Spleen 7,727 (1288) 4.2 (0.9) Lung 27,013 (2896) 11.3 (4.3) Heart 11,737 (3491) 10.0 (1.9) Kidneys 17,413 (6581) 8.5 (2.0) Citation Format: Pujan Desai, Maithili Rairkar, Nela Pawlowska, Scott Thomas, Pamela N. Munster. Prostate specific sustained anti androgen delivery to delay early stage prostate cancer progression. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5261.

Molecular basis and therapeutic targets in prostate cancer: A comprehensive review.

Prostate cancer is one of the most significant causes of morbidity and mortality in male patients. The incidence increases with age, and it is higher among African Americans. The occurrence of prostate cancer is associated with many risk factors, including genetic and hereditary predisposition. The most common genetic syndromes associated with prostate cancer risk are BRCA-associated hereditary breast and ovarian cancer (HBOC) and Lynch syndrome. Local-regional therapy, i.e., surgery is beneficial in early-stage prostate cancer management. Advanced and metastatic prostate cancers require systemic therapies, including hormonal inhibition, chemotherapy, and targeted agents. Most prostate cancers can be treated by targeting the androgen-receptor pathway and decreasing androgen production or binding to androgen receptors (AR). Castration-resistant prostate cancer (CRPC) usually involves the PI3K/AKT/mTOR pathway and requires targeted therapy. Specific molecular therapy can target mutated cell lines in which DNA defect repair is altered, caused by mutations ofBRCA2, partner and localizer of BRCA2 (PALB2), and phosphatase and tensin homolog (PTEN) or the transmembrane protease serine 2-ERG (TMPRSS2-ERG)fusion. Most benefits were demonstrated incyclin dependent-kinase 12 (CDK12)mutated cell lines when treated with anti-programmed cell death protein 1 (PD1) therapy. Therapies targetingp53and AKT are the subject of ongoing clinical trials. Many genetic defects are listed as diagnostic, prognostic, and clinically actionable markers in prostate cancer. Androgen receptor splice variant 7 (AR-V7) is an important oncogenic driver and an early diagnostic and prognostic marker, as well as a therapeutic target in hormone-resistant CRPC. This review summarizes the pathophysiological mechanisms and available targeted therapies for prostate cancer.

MP80-03 OPIOID USE IN VETERANS WITH PROSTATE CANCER FOLLOWING SURGERY TREATMENT

You have accessJournal of UrologyCME1 Apr 2023MP80-03 OPIOID USE IN VETERANS WITH PROSTATE CANCER FOLLOWING SURGERY TREATMENT Sumedha Chhatre, S Bruce Malkowicz, Thomas Guzzo, Marilyn Schapira, and Ravishankar Jayadevappa Sumedha ChhatreSumedha Chhatre More articles by this author , S Bruce MalkowiczS Bruce Malkowicz More articles by this author , Thomas GuzzoThomas Guzzo More articles by this author , Marilyn SchapiraMarilyn Schapira More articles by this author , and Ravishankar JayadevappaRavishankar Jayadevappa More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003357.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Opioid use for pain management in cancer patients is a challenge. Study objective was to determine the incidence of persistent opioid use in Veterans with early stage prostate cancer and treated with surgery. METHODS: Retrospective cohort study of Veterans diagnosed with prostate cancer between 2015 and 2016. Opioid exposure attributable to treatment was defined as the cumulative oral or topical Morphine Milligram Equivalents (MMEs) prescribed from 31 days prior to 14 days post index surgery. Outcome was any opioid use in the 13-month follow-up period. Eligibility criteria was Veterans receiving care at a VA Medical Center, aged ≥21 years, early stage prostate cancer, surgery treatment at VA Medical Center, and opioid naïve in the period 12 months to 31 days prior to index surgery. Logistic regression was used to model association between any opioid use in the follow-up period as a function of any baseline opioid use, baseline opioid use (MMEs), age, race, ethnicity, socio-economic status, dual enrollment-Medicare Part D, comorbidity, mental health conditions, chronic pain, non-opioid pain medications, cancer treatment (adjuvant chemotherapy, radiation, immunotherapy), and district. RESULTS: 2,594 Veterans with prostate cancer met our criteria. Proportion of Veterans with opioid use during the 13-moth follow-up period is shown in Table 1. The largest opioid use was observed in the first follow-up month (31.5%), and 42.5% had at least one month of opioid use in the follow-up period. Baseline opioid use (OR=5.3, 95% CI=4.1, 6.9), diagnosis year 2015 (OR=1.6, 95% CI=1.3, 1.9), Elixhauser comorbidity score of 1-3 (OR=1.9, 95% CI=1.4, 2.7), chronic pain (OR=1.4, 95% CI=1.2, 1.7), anxiety, depression or PTSD (OR=1.4, 95% CI=1.1, 1.8), and Pacific district were associated with higher risk of opioid use in the follow-up period. Dual Medicare enrollment (OR=0.73, 95% CI=0.57, 0.94), and cancer stage I (OR=0.44, 95% CI=0.30, 0.63) were associated with lower risk of opioid use in follow-up period. CONCLUSIONS: Opioid use immediately after surgery was associated with continued opioid use in the follow-up period. This has implications for optimizing pain management for Veterans with prostate cancer. Source of Funding: VA HSR&D PPO 20-121 and DoD W81XWH-19-1-0461 © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e1152 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Sumedha Chhatre More articles by this author S Bruce Malkowicz More articles by this author Thomas Guzzo More articles by this author Marilyn Schapira More articles by this author Ravishankar Jayadevappa More articles by this author Expand All Advertisement PDF downloadLoading ...

MP38-12 PERSISTENT NEED FOR SYSTEMATIC BIOPSY FOR MEN ON ACTIVE SURVEILLANCE FOR EARLY-STAGE PROSTATE CANCER

You have accessJournal of UrologyCME1 Apr 2023MP38-12 PERSISTENT NEED FOR SYSTEMATIC BIOPSY FOR MEN ON ACTIVE SURVEILLANCE FOR EARLY-STAGE PROSTATE CANCER Mary Fakunle, Janet Cowan, Samuel Washington, Katsuto Shinohara, Hao Nguyen, Matthew Cooperberg, and Peter Carroll Mary FakunleMary Fakunle More articles by this author , Janet CowanJanet Cowan More articles by this author , Samuel WashingtonSamuel Washington More articles by this author , Katsuto ShinoharaKatsuto Shinohara More articles by this author , Hao NguyenHao Nguyen More articles by this author , Matthew CooperbergMatthew Cooperberg More articles by this author , and Peter CarrollPeter Carroll More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003276.12AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Serial biopsy is a mainstay of surveillance for patients on active surveillance for prostate cancer. mpMRI targeting has become a standard for targeting lesions during biopsy as it allows for better identification of the dominant lesion (grade and/or volume). It is unclear whether “targeted biopsy” alone reliably identifies the dominant lesion on serial biopsy, thereby obviating the need for systematic biopsy. The aim of this study was to assess whether targeting alone can consistently identify the dominant lesion on serial biopsies for active surveillance. METHODS: Participants enrolled in active surveillance with early-stage prostate cancer (PSA <20, cT1-2, GG1 and 2) at diagnosis and underwent two or more MR fusion biopsy sessions that include both systematic and targeted sampling. Timing and frequency of Gleason upgrading were assessed. Grade and sextant location within the prostate were compared between the systematic and targeted cores to determine concordance. RESULTS: Of 619 men who had multiple MR targeted biopsies, 80% were GG 1 at time of diagnosis and 20% were GG 2. Fifteen percent had their first MR fusion biopsy as their diagnostic, 41% on confirmatory biopsy, and 44% on subsequent surveillance biopsy. The highest grade was sampled by MR targeting from 70% to 91% of the time. In a subset of 106 men with GG1 at first MR fusion biopsy and a subsequent MR fusion biopsy within 36 months, Gleason upgrading was detected in 47 men (44%) on the 2nd MR fusion biopsy. When comparing upgrading between systematic and MRI targeting, 20 men (42%) upgraded inside the target only. Twenty-one men (45%) upgraded on both systematic and MR targeted biopsy. And 6 men (13%) upgraded on systematic biopsy only. CONCLUSIONS: In those with serial MR-targeted biopsies, targeting alone identified a majority of upgrading. However, it missed a portion of those with upgrading outside the target. This suggests that those on active surveillance, with MR targets, still benefit from systematic biopsies. Source of Funding: UCSF Goldberg-Benioff Program in Translational Cancer Biology © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e528 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Mary Fakunle More articles by this author Janet Cowan More articles by this author Samuel Washington More articles by this author Katsuto Shinohara More articles by this author Hao Nguyen More articles by this author Matthew Cooperberg More articles by this author Peter Carroll More articles by this author Expand All Advertisement PDF downloadLoading ...

PD04-11 MCT INHIBITION RESENSITIZES ENZALUTAMIDE-RESISTANT PROSTATE CANCER CELLS TO ENZALUTAMIDE

You have accessJournal of UrologyCME1 Apr 2023PD04-11 MCT INHIBITION RESENSITIZES ENZALUTAMIDE-RESISTANT PROSTATE CANCER CELLS TO ENZALUTAMIDE Sayani Bhattacharjee, Rebecca Wynn, Puneet Sindhwani, Firas Petros, and Nagalakshmi Nadiminty Sayani BhattacharjeeSayani Bhattacharjee More articles by this author , Rebecca WynnRebecca Wynn More articles by this author , Puneet SindhwaniPuneet Sindhwani More articles by this author , Firas PetrosFiras Petros More articles by this author , and Nagalakshmi NadimintyNagalakshmi Nadiminty More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003228.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Prostate cancers (PCa) exhibit a unique metabolic profile with reliance on different forms of glucose metabolism at different stages of disease progression. Early stage PCa cells use the more efficient TCA cycle, while metastatic PCa cells switch to glycolysis (Warburg effect), leading to the accumulation of lactate. Monocarboxylate transporters (MCTs) play a major role in the export/import of lactate to maintain redox balance. Such metabolic reprogramming can lead to gain-of-function mutations and affect drug sensitivity. MCT expression levels are high in enzalutamide-resistant PCa cells. Hence, we hypothesized that MCT inhibition may be an attractive therapeutic strategy to overcome enzalutamide resistance in PCa cells. METHODS: We analyzed the expression levels of MCTs in PCa tissues using public datasets from Oncomine. We treated C4-2B and 22Rv1 parental and enzalutamide-resistant cells with varying concentrations of MCT inhibitors AR-C155858, AZD3965, or syrosingopine either singly or in combination with enzalutamide and assessed cell survival, cell viability, proliferation, clonogenic ability, survival in 3-D models, and glycolytic activity. We treated mouse xenografts of PCa cells with MCT inhibitors or enzalutamide either singly or in combination and assessed tumor growth. RESULTS: We found that the suppression of MCT activity using the MCT antagonists AR-C155858, AZD3965, or syrosingopine significantly diminished the proliferation, survival, and clonogenic ability of enzalutamide-resistant PCa cells compared with parental cells. MCT inhibition in combination with enzalutamide inhibited the metabolic adaptation of PCa cells. Tumor growth of enzalutamide-resistant PCa cell xenografts was suppressed significantly when treated with a combination of MCT inhibitors with enzalutamide. These findings imply that MCT inhibition may be an effective strategy to counter enzalutamide resistance in PCa. CONCLUSIONS: MCT activation may underlie the development of enzalutamide resistance in PCa and targeting it may represent a viable combinatorial option. Source of Funding: Department of Defense Prostate Prostate Cancer Research Program W81XWH2010794 (PC190332) © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e146 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Sayani Bhattacharjee More articles by this author Rebecca Wynn More articles by this author Puneet Sindhwani More articles by this author Firas Petros More articles by this author Nagalakshmi Nadiminty More articles by this author Expand All Advertisement PDF downloadLoading ...

Persistent need for systematic biopsy for those on active surveillance for early-stage prostate cancer.

322 Background: Serial biopsy is a mainstay of surveillance for patients on active surveillance for prostate cancer. mpMRI targeting has become a standard for targeting lesions during biopsy as it allows for better identification of the dominant lesion (grade and/or volume). It is unclear whether “targeted biopsy” alone reliably identifies the dominant lesion on serial biopsy, thereby obviating the need for systematic biopsy. The aim of this study was to assess whether targeting alone can consistently identify the dominant lesion on serial biopsies for active surveillance. Methods: Participants enrolled in active surveillance with early-stage prostate cancer (PSA &lt;20, cT1-2, GG1 and 2) at diagnosis and underwent two or more MR fusion biopsy sessions that include both systematic and targeted sampling. Timing and frequency of Gleason upgrading were assessed. Grade and sextant location within the prostate were compared between the systematic and targeted cores to determine concordance. Results: Of 619 men who had multiple MR targeted biopsies, 80% were GG 1 at time of diagnosis and 20% were GG 2. Fifteen percent had their first MR fusion biopsy as their diagnostic, 41% on confirmatory biopsy, and 44% on subsequent surveillance biopsy. The highest grade was sampled by MR targeting from 70% to 91% of the time. In a subset of 106 men with GG1 at first MR fusion biopsy and a subsequent MR fusion biopsy within 36 months, Gleason upgrading was detected in 47 men (44%) on the 2nd MR fusion biopsy. When comparing upgrading between systematic and MRI targeting, 20 men (42%) upgraded inside the target only. Twenty-one men (45%) upgraded on both systematic and MR targeted biopsy. And 6 men (13%) upgraded on systematic biopsy only. Conclusions: In those with serial MR-targeted biopsies, targeting alone identified a majority of upgrading. However, it missed a portion of with upgrading outside the target. This suggests that those on active surveillance, with MR targets, still benefit from systematic biopsies.

Predictor of adverse pathology in patients who underwent deferred radical prostatectomy following active surveillance: Results from multi-institutional prospective observational cohort in the PRIAS-JAPAN.

350 Background: Intraductal carcinoma of the prostate (IDC-P) and invasive cribriform are key prognostic pathologies among early stage prostate cancer patients; however, predictors of adverse pathology, including these types, remain unknown. In men who opted for active surveillance (AS), we aimed to examine the association between adverse pathology and patient characteristics, utilizing radical prostatectomy (RP) specimens. Methods: We re-reviewed available RP specimens from 1035 men prospectively enrolled in the PRIAS-JAPAN cohort between January 2010 and September 2020. We defined adverse pathology on RP specimen as Gleason grade group of ≥3, pT-stage≥T3, pN positivity, or the presence of IDC-P or invasive cribriform. And, we examined the predictive factors associated with adverse pathology, using factors at AS enrollment and before RP. Results: Out of 162 men underwent RP, available 137 RP specimens were analyzed. The percentage of adverse pathology was 48.9% (67 patients), including 8.8% in IDC-P and 29.9 % in invasive cribriform. Men with adverse pathology had lower prostate specific antigen recurrence-free survival than those without them (log rank P = 0.0189). On multivariate logistic regression analyses, increasing age at AS enrollment and before RP were the predictive factors for adverse pathology (Odds ratio [OR], 1.1; 95% confidence interval [CI]: 1.02-1.19, P = 0.0178, OR, 1.12; 95% CI: 1.02-1.22, P=0.0126), not magnetic resonance imaging findings. Conclusions: Aging is significantly associated with adverse pathology including IDC-P or cribriform. The results suggest that relaxing scheduled examinations during AS depending on age is not practical. Clinical trial information: UMIN000048095 .

Potential New Approaches for Prostate Cancer Management in Resource-Limited Countries in Africa.

Prostate cancer is a major male malignancy in many sub-Saharan countries in Africa. Because of resource limitations, screening, early detection, diagnosis, and curative treatments are not available for many men on the subcontinent, and there are even barriers to the treatment of advanced-stage metastatic prostate cancer. We are making the case for new approaches to the detection, diagnosis, and treatment of this malignancy in sub-Saharan Africa and other low-resource regions-approaches that differ from the ones available and used in high-income countries. The development of one-step dipstick-type detection assays of serum prostate-specific antigen (PSA) offers an approach to prostate cancer detection, treatment and monitoring that circumvents issues related to laboratory quality control and is also low-cost. Curative-intent treatments of early-stage prostate cancer are often unavailable in low-resource contexts, and most prostate cancers are not detected in Africa until they are at an advanced stage. Hence, androgen deprivation treatments, including orchiectomy and older low-cost drugs, offer feasible and affordable approaches to prolong survival and sustain a reasonable quality of life. However, clinical trials are needed to identify which of these androgen deprivation treatments are most efficacious and best tolerated to make progress in providing medical care for men with prostate cancer in sub-Saharan Africa and other low- and lower-middle-income areas around the world.

Development and clinical validation of a novel biopsy-based six-gene signature to accurately risk-stratify men with early-stage prostate cancer to aid treatment decision making.

374 Background: Prostate cancer (PCa) is diagnosed in over 1.2 million men worldwide annually, making it the second-most common non-cutaneous cancer in men. Most men have indolent PCa and can safely defer treatment with active surveillance. However, many patients are commonly treated with surgery (radical prostatectomy, RP) or radiation therapy, which are associated with a significant reduction in quality of life. Molecular signatures have been developed to assist clinicians in stratifying patients based on their risk of aggressive PCa; while these have shown promise, there remains a significant opportunity for improving prognostic capacity. Methods: A panel of fourteen prognostic genes was identified from The Cancer Genome Atlas Prostate Adenocarcinoma (TCGA PRAD) database. Gene expression was measured by reverse-transcription quantitative polymerase chain reaction in RP samples from an Irish cohort of men diagnosed with PCa and treated with RP (PCRC, n=426). Cross-validated logistic regression analysis identified a six-gene molecular risk score (MRS) with strong prognostic performance to predict aggressive PCa, i.e., adverse pathology (AP) at RP or biochemical recurrence (BCR). The MRS was combined with the Cancer of the Prostate Risk Assessment (CAPRA) score to create a molecular plus clinical risk score (MCRS). The MRS and MCRS were clinically validated in biopsy samples from an independent Swedish cohort of men diagnosed with PCa and treated by RP (UPCA, n=100). Results: We identified a six-gene signature, consisting of four prognostic and two reference genes, with improved prognostic value over clinical features. In the clinical biopsy validation study univariable analysis, the AUC of the signature for AP was 0.72 (MRS) and 0.82 (MCRS) versus 0.72 for EAU risk categories and 0.82 for CAPRA. The C-index for BCR was 0.62 (MRS) and 0.74 (MCRS) versus 0.65 for EAU risk categories and 0.73 for CAPRA. Furthermore, in bivariable analysis, the six-gene signature added statistically significant (p &lt; 0.001) prognostic value to EAU risk categories and CAPRA. Conclusions: The six-gene prognostic signature has strong performance for AP and BCR in an independent clinical biopsy validation study. MCRS can provide improved prognostic stratification and inform optimal patient management post-diagnosis.

Could Biparametric MRI Replace Multiparametric MRI in the Management of Prostate Cancer?

Prostate cancer (PCa) is a worldwide epidemiological problem, since it is one of the most prevalent types of neoplasia among men, and the third-leading cause of cancer-related deaths, after lung and colorectal tumors. Unfortunately, the early stages of PCa have a wide range of unspecific symptoms. For these reasons, early diagnosis and accurate evaluation of suspicious lesions are crucial. Multiparametric MRI (mpMRI) is currently the imaging modality of choice for diagnostic screening and local staging of PCa, but also has a leading role in guiding biopsies and in treatment biparametric MRI (bpMRI) could partially replace mpMRI due to its lack of adverse reactions caused by contrast agents, relatively lower costs, and shorter acquisition time. Further, 31 relevant articles regarding the advantages and disadvantages of the aforementioned imaging techniques were scanned. As a result, while bpMRI has comparable accuracy in detecting PCa, its roles in the other steps of PCa management are limited.

Identification of Promising Drug Candidates against Prostate Cancer through Computationally-Driven Drug Repurposing.

Prostate cancer (PC) is one of the most common types of cancer in males. Although early stages of PC are generally associated with favorable outcomes, advanced phases of the disease present a significantly poorer prognosis. Moreover, currently available therapeutic options for the treatment of PC are still limited, being mainly focused on androgen deprivation therapies and being characterized by low efficacy in patients. As a consequence, there is a pressing need to identify alternative and more effective therapeutics. In this study, we performed large-scale 2D and 3D similarity analyses between compounds reported in the DrugBank database and ChEMBL molecules with reported anti-proliferative activity on various PC cell lines. The analyses included also the identification of biological targets of ligands with potent activity on PC cells, as well as investigations on the activity annotations and clinical data associated with the more relevant compounds emerging from the ligand-based similarity results. The results led to the prioritization of a set of drugs and/or clinically tested candidates potentially useful in drug repurposing against PC.

Poorly Controlled Diabetes Mellitus Increases the Risk of Deaths and Castration-Resistance in Locally Advanced Prostate Cancer Patients

The association between DM and prostate cancer progression remains controversial. Previous studies mainly focused on early stage prostate cancer patients. We aimed to study the association between DM and prostate cancer progression in locally advanced prostate cancer patients. 598 locally advanced prostate cancer patients in a top tertiary hospital in China between 2012 and 2021 were divided into three groups based on the postoperative average HbA1c level. The follow-up time is 46.96 ± 27.07 months. Three hundred and forty-eight (58.2%) were normal glucose, 175 (29.3%) were moderate glucose, and 75 (12.5%) were high glucose. Higher postoperative-average HbA1c was associated with poorer OS, PCSM, and PSA-RFS. We concluded that poorly controlled DM was correlated with poorer OS, PCSM, and PSA-RFS in locally advanced prostate cancer patients.

Enzalutamide induced non-ischemic cardiomyopathy. A case report and review of literature on anti-androgen therapy-related cardiovascular events

Prostate cancer has a very high prevalence among elder men, and this could potentially increase as longevity in many parts of the world is increasing. Early stages of prostate cancer can have surgical options, but the more advanced stages require some form of anti-androgen therapy. There are novel anti-androgen agents that were recently approved. Cardiovascular toxicity has been reported with some of these drugs. This is a novel report of likely cardiovascular toxicity due to Enzalutamide, which typically has a safer cardiovascular profile than Abiraterone.We describe a 72-year-old male with repeated recurrence of prostate cancer with metastasis. The second time it recurred was within 2 years of the 1st recurrence and was treated with Enzalutamide.However, within 2 weeks he developed systolic congestive heart failure that improved with stopping the drug and medical optimization.Literature review shows that Abiraterone has more cardiovascular side effects than Enzalutamide which more commonly causes hypertension. The timeline in our case suggests Enzalutamide causing congestive heart failure which is a novel finding. This finding warrants further research regarding the safety profile of novel anti-androgen therapy. This includes risk stratification for potential cardiovascular adverse events and risk/benefit analysis prior to initiating therapy. Data on cumulative dose accumulation and risks can also be an area of future research.

Cancer beliefs and diet self-management among cancer survivors with comorbid diabetes.

Illness beliefs impact disease self-management; however, little is known about the impact of patients' beliefs about one illness on the management of another illness. We sought to understand how cancer beliefs impact diet self-management for cancer survivors with diabetes and whether a change in beliefs leads to a change in dietary adherence. Seventy-eight participants with diabetes and recently diagnosed early-stage breast, prostate, lung, or colon cancer were recruited. Participants were surveyed at enrollment and after 12months about their cancer and diabetes illness beliefs and dietary adherence. Associations between beliefs about cancer and diabetes to diet adherence at baseline and at 12months were assessed. Change in diet adherence was examined in relation to beliefs about each illness. The mean age was 62years, and 23 (32%) identified as black non-Hispanic, 22 (31%) as white non-Hispanic, and 14 (19%) as Hispanic. Participants with more threatening beliefs about both cancer and diabetes at baseline had worse adherence to a diabetes diet than those with less threatening beliefs. However, at 12months, those with more threatening cancer beliefs had better dietary adherence than participants with less threatening beliefs. Diabetes beliefs were not associated with diet adherence at 12months. While threatening illness beliefs may initially result in worse diet adherence, over time these beliefs may result in increased activation for better self-care and improved diet adherence. Understanding how cancer beliefs impact diet self-management for diabetes may provide coping strategies to improve cancer survivors' management of comorbidities.

PSMA-PET in the early stages of prostate cancer

PSMA-PET in the early stages of prostate cancer