LX1 Dual Targets AR Variants and AKR1C3 in Advanced Prostate Cancer Therapy.

The development of resistance to current standard-of-care treatments, such as androgen receptor (AR) targeting therapies, remains a major challenge in the management of advanced prostate cancer. There is an urgent need for new therapeutic strategies targeting key resistant drivers, such as AR variants like AR-V7, and steroidogenic enzymes, such as aldo-keto reductase 1C3 (AKR1C3), to overcome drug resistance and improve outcomes for patients with advanced prostate cancer. Here, we have designed, synthesized, and characterized a novel class of LX compounds targeting both the AR/AR variants and AKR1C3 pathways.

IGFBP3 promotes resistance to Olaparib via modulating EGFR signaling in advanced prostate cancer.

Olaparib is a pioneering PARP inhibitor (PARPi) approved for treating castration-resistant prostate cancer (CRPC) tumors harboring DNA repair defects, but clinical resistance has been documented. To study acquired resistance, we developed Olaparib-resistant (OlapR) cell lines through chronic Olaparib treatment of LNCaP and C4-2B cell lines. Here, we found that IGFBP3 is highly expressed in acquired (OlapR) and intrinsic (Rv1) models of Olaparib resistance.

Olaparib-Induced Senescence Is Bypassed through G2-M Checkpoint Override in Olaparib-Resistant Prostate Cancer.

PARP inhibition represents the dawn of precision medicine for treating prostate cancer. Despite this advance, questions remain regarding the use of PARP inhibitors (PARPi) for the treatment of this disease, including (i) how specifically do PARPi-sensitive tumor cells respond to treatment, and (ii) how does PARPi resistance develop? To address these questions, we characterized response to olaparib in sensitive LNCaP and C4-2B cells and developed two olaparib-resistant derivative cell line models from each, termed LN-OlapR and 2B-OlapR, respectively. OlapR cells possess distinct morphology from parental cells and display robust resistance to olaparib and other clinically relevant PARPis, including rucaparib, niraparib, and talazoparib.

Dysregulated androgen synthesis and anti-androgen resistance in advanced prostate cancer.

Current therapies for treating castration resistant prostate cancer (CRPC) include abiraterone and enzalutamide which function by inhibiting androgen signaling by targeting androgen synthesis and antagonizing the androgen receptor (AR) respectively. While these therapies are initially beneficial, resistance inevitably develops. A number of pathways have been identified to contribute to CRPC progression and drug resistance.

Integrated exome and RNA sequencing of TFE3-translocation renal cell carcinoma.

TFE3-translocation renal cell carcinoma (TFE3-tRCC) is a rare and heterogeneous subtype of kidney cancer with no standard treatment for advanced disease. We describe comprehensive molecular characteristics of 63 untreated primary TFE3-tRCCs based on whole-exome and RNA sequencing. TFE3-tRCC is highly heterogeneous, both clinicopathologically and genotypically.

Activation of the Amplicon in Docetaxel- and Cabazitaxel-Resistant Prostate Cancer Cells.

Docetaxel and cabazitaxel-based taxane chemotherapy are critical components in the management of advanced prostate cancer. However, their efficacy is hindered due to presentation with or the development of resistance. Characterizing models of taxane-resistant prostate cancer will lead to creation of strategies to overcome insensitivity.

ARVib suppresses growth of advanced prostate cancer via inhibition of androgen receptor signaling.

Targeting androgen signaling with the second-generation anti-androgen drugs, such as enzalutamide (Enza), abiraterone (Abi), apalutamide (Apal), and darolutamide (Daro), is the mainstay for the treatment of castration-resistant prostate cancer (CRPC). While these treatments are effective initially, resistance occurs frequently. Continued expression of androgen receptor (AR) and its variants such as AR-V7 despite AR-targeted therapy contributes to treatment resistance and cancer progression in advanced CRPC patients.

Circulating tumour DNA reveals genetic traits of patients with intraductal carcinoma of the prostate.

Objectives: To investigate the genetic alterations of patients with prostate cancer (PCa) with and without intraductal carcinoma of the prostate (IDC-P).

Patients And Methods: We performed targeted sequencing of plasma cell-free DNA on 161 patients with prostate adenocarcinoma (PAC) with IDC-P and 84 without IDC-P. Genomic alterations were compared between these two groups.

Integrated Molecular Characterization of Fumarate Hydratase-deficient Renal Cell Carcinoma.

Purpose: Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare but lethal subtype of RCC. Little is known about the genomic profile of FH-deficient RCC, and the therapeutic options for advanced disease are limited. To this end, we performed a comprehensive genomics study to characterize the genomic and epigenomic features of FH-deficient RCC.

Steroid Sulfatase Stimulates Intracrine Androgen Synthesis and is a Therapeutic Target for Advanced Prostate Cancer.

Purpose: Most patients with prostate cancer receiving enzalutamide or abiraterone develop resistance. Clinical evidence indicates that serum levels of dehydroepiandrosterone sulfate (DHEAS) and biologically active DHEA remain in the high range despite antiandrogen treatment. The conversion of DHEAS into DHEA by steroid sulfatase (STS) may contribute to sustained intracrine androgen synthesis.

Cross-Resistance Among Next-Generation Antiandrogen Drugs Through the AKR1C3/AR-V7 Axis in Advanced Prostate Cancer.

The next-generation antiandrogen drugs, XTANDI (enzalutamide), ZYTIGA (abiraterone acetate), ERLEADA (apalutamide) and NUBEQA (darolutamide) extend survival times and improve quality of life in patients with advanced prostate cancer. Despite these advances, resistance occurs frequently and there is currently no definitive cure for castration-resistant prostate cancer. Our previous studies identified that similar mechanisms of resistance to enzalutamide or abiraterone occur following treatment and cross-resistance exists between these therapies in advanced prostate cancer.

Wntless promotes cellular viability and resistance to enzalutamide in castration-resistant prostate cancer cells.

Background: De-regulation of Wnt signaling pathways has been shown to be associated with progression of castration-resistant prostate cancer and more recently, studies indicate that both canonical and non-canonical Wnt pathways may mediate resistance to anti-androgen therapies such as enzalutamide. However, the mechanisms by which Wnt signaling is altered in prostate cancer remain poorly understood. Wnt pathway function begins with Wnt biogenesis and secretion from Wnt signal sending cells.

AKR1C3 Promotes AR-V7 Protein Stabilization and Confers Resistance to AR-Targeted Therapies in Advanced Prostate Cancer.

The mechanisms resulting in resistance to next-generation antiandrogens in castration-resistant prostate cancer are incompletely understood. Numerous studies have determined that constitutively active androgen receptor (AR) signaling or full-length AR bypass mechanisms may contribute to the resistance. Previous studies established that AKR1C3 and AR-V7 play important roles in enzalutamide and abiraterone resistance.

AKR1C3 expression in primary lesion rebiopsy at the time of metastatic castration-resistant prostate cancer is strongly associated with poor efficacy of abiraterone as a first-line therapy.

Background: Previous studies had demonstrated that aldo-keto reductase family 1 member C3 (AKR1C3), a crucial enzyme in the steroidogenic pathway, played an important role in abiraterone (ABI)-resistance in metastatic castration-resistant prostate cancer (mCRPC) by increasing intratumoral androgen synthesis. However, its value in predicting treatment response in patients with mCRPC is unknown.

Method And Materials: Data of 163 patients with metastatic prostate cancer between 2016 and 2018 were retrospectively analyzed.

Overexpressed ABCB1 Induces Olaparib-Taxane Cross-Resistance in Advanced Prostate Cancer.

Castration-resistant prostate cancer remains as an incurable disease. Exploiting DNA damage repair defects via inhibition of poly (ADP-ribose) polymerase (PARP) is becoming an attractive therapeutic option. The TOPARP-A clinical trial demonstrated that the PARP inhibitor olaparib may be an effective strategy for treating prostate cancer.

Current strategies for targeting the activity of androgen receptor variants.

Current therapies for advanced prostate cancer, such as enzalutamide and abiraterone, focus on inhibiting androgen receptor (AR) activity and reducing downstream signaling pathways to inhibit tumor growth. Unfortunately, cancer cells are very adaptable and, over time, these cells develop mechanisms by which they can circumvent therapeutics. One of the many mechanisms that have been discovered is the generation of AR variants.

Proteostasis by STUB1/HSP70 complex controls sensitivity to androgen receptor targeted therapy in advanced prostate cancer.

Protein homeostasis (proteostasis) is a potential mechanism that contributes to cancer cell survival and drug resistance. Constitutively active androgen receptor (AR) variants confer anti-androgen resistance in advanced prostate cancer. However, the role of proteostasis involved in next generation anti-androgen resistance and the mechanisms of AR variant regulation are poorly defined.

Novel nomograms for castration-resistant prostate cancer and survival outcome in patients with de novo bone metastatic prostate cancer.

Objectives: To develop nomograms predicting the incidence of castration-resistant prostate cancer (CRPC) and overall survival (OS) for de novo metastatic prostate cancer (PCa).

Patients And Methods: Data from 449 patients with de novo metastatic PCa were retrospectively analysed. Patients were randomly divided into a training (n = 314, 70%) and a validation cohort (n = 135, 30%).

ABCB1 Mediates Cabazitaxel-Docetaxel Cross-Resistance in Advanced Prostate Cancer.

Advancements in research have added several new therapies for castration-resistant prostate cancer (CRPC), greatly augmenting our ability to treat patients. However, CRPC remains an incurable disease due to the development of therapeutic resistance and the existence of cross-resistance between available therapies. Understanding the interplay between different treatments will lead to improved sequencing and the creation of combinations that overcome resistance and prolong survival.

Adaptive pathways and emerging strategies overcoming treatment resistance in castration resistant prostate cancer.

The therapies available for prostate cancer patients whom progress from hormone-sensitive to castration resistant prostate cancer include both systemic drugs, including docetaxel and cabazitaxel, and drugs that inhibit androgen signaling such as enzalutamide and abiraterone. Unfortunately, it is estimated that up to 30% of patients have primary resistance to these treatments and over time even those who initially respond to therapy will eventually develop resistance and their disease will continue to progress regardless of the presence of the drug. Determining the mechanisms involved in the development of resistance to these therapies has been the area of intense study and several adaptive pathways have been uncovered.

Estradiol Has Differential Effects on Acute Colonic Inflammation in the Presence and Absence of Estrogen Receptor β Expression.

Background: Inflammatory bowel disease (IBD) increases the risk of developing colon cancer. This risk is higher in men compared to women, implicating a role for female hormones in the protection against this disease. Studies from our laboratory demonstrated that estradiol (E) protects against inflammation-associated colon tumor formation when administered following chemical carcinogen and induction of chronic colitis.

Niclosamide and Bicalutamide Combination Treatment Overcomes Enzalutamide- and Bicalutamide-Resistant Prostate Cancer.

Activation of the androgen receptor (AR) and its splice variants is linked to advanced prostate cancer and drives resistance to antiandrogens. The roles of AR and AR variants in the development of resistance to androgen deprivation therapy (ADT) and bicalutamide treatment, however, are still incompletely understood. To determine whether AR variants play a role in bicalutamide resistance, we developed bicalutamide-resistant LNCaP cells (LNCaP-BicR) and found that these resistant cells express significantly increased levels of AR variants, particularly AR-V7, both at the mRNA and protein levels.

MicroRNA-181a promotes docetaxel resistance in prostate cancer cells.

Background: Docetaxel is one of the primary drugs used for treating castration resistant prostate cancer (CRPC). Unfortunately, over time patients invariably develop resistance to docetaxel therapy and their disease will continue to progress. The mechanisms by which resistance develops are still incompletely understood.

CCN3-EZH2-AR feedback loop: new targets for enzalutamide and castration resistant prostate cancer.

The development of castration resistant prostate cancer and anti-androgen resistance remains one of the largest hurdles in the successful treatment of prostate cancer. Therefore, the identification of dysregulated pathways contributing to this resistance and determining ways to target these mechanisms is of utmost importance. In the recent publication in Cancer Research, Fong et al.