Novel Target Opportunities in Non-Metastatic Castrate Resistant Prostate Cancer.
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ABSTRACT:
SUBMITTER: Gleicher S
PROVIDER: S-EPMC8157020 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Recent advances in tumor biology have made remarkable achievements in the development of therapy for metastatic castrate-resistant prostate cancer. These advances reflect a growing appreciation for the role of the tumor microenvironment in promoting prostate cancer progression. Prostate cancer is no longer viewed predominantly as a disease of abnormally proliferating epithelial cells but rather as a disease of complex interactions between prostate cancer epithelial cells (epithelial compartment) and the surrounding tissues (stromal compartment) in which they reside. For example, prostate cancers frequently metastasize to bone, an organ that contains a microenvironment rich in extracellular matrix proteins and stromal cells including hematopoietic cells, osteoblasts, osteoclasts fibroblasts, endothelial cells, adipocytes, immune cells, and mesenchymal stem cells. Multiple signaling pathways provide crosstalk between the epithelial and the stromal compartments to enhance tumor growth, including androgen receptor signaling, tyrosine kinase receptor signaling, and immune surveillance. The rationale to disrupt this "two-compartment" crosstalk has led to the development of drugs that target tumor stromal elements in addition to the cancer epithelial cell.
| S-EPMC4176261 | biostudies-literature
Project description:Treatment options for castrate-resistant prostate cancer (CRPC) have advanced in recent years and significantly improved the outlook for patients with this aggressive and lethal disease. Further understanding of the biology of CRPC has led to several new targeted therapies and continues to emphasize the importance of androgen receptor (AR) directed therapy. The treatment landscape is rapidly changing and further biologically rationale, biomarker-based ongoing clinical trials are needed. We review the recent results of major clinical trials in CRPC. New and investigational agents now in clinical evaluation are reviewed including inhibitors of angiogenesis, microtubules, chaperones, AR and intracellular kinases, as well as immunotherapy, radiopharmaceuticals and bone-targeted agents. The recent improvement in prognosis for CRPC brings continued optimism for further improvements. Thoughtful planning of clinical trials and further understanding of the mechanisms of resistance to therapies will allow for continued progress in patient care.
| S-EPMC3739642 | biostudies-literature
Project description:Castrate resistant prostate cancer (CRPC) remains a disease with significant morbidity and mortality. The recent approval of abiraterone and enzalutamide highlight the improvements which can be made targeting the androgen receptor (AR) axis. Nonetheless, resistance inevitably develops and there is continued interest in targeting alternate pathways which cause disease resistance and progression. Here, we review non-AR targets in CRPC, with an emphasis on novel agents now in development. This includes therapeutics which target the tumour microenvironment, the bone metastatic environment, microtubules, cellular energetics, angiogenesis, the stress response, survival proteins, intracellular signal transduction, DNA damage repair and dendritic cells. Understanding the hallmarks of prostate cancer resistance in CRPC has led to the identification and development of these new targets. We review the molecular rationale, as well at the clinical experience for each of these different classes of agents which are in clinical development.
| S-EPMC4708177 | biostudies-literature
Project description:The majority of patients with castrate-resistant prostate cancer will have metastatic disease at the time of diagnosis. Investigative efforts on new therapeutics for this patient population have improved with the development of androgen signaling inhibitors, such as abiraterone and enzalutamide, and PARP inhibitors, such as rucaparib and olaparib, to accompany the previously FDA-approved docetaxel, cabazitaxel, sipuleucel-T, and Radium 223. However, new therapeutic strategies are necessary to prolong survival as progression after these agents is inevitable. CDK4/6 inhibitors have advanced the field of estrogen receptor positive breast cancer treatment and are being investigated in prostate cancer given the role of androgen receptor signaling effects on the cell cycle. Response to CDK4/6 inhibitors may be predicted by the tumors' genomic profile and may provide insight into combinatory therapy with CDK4/6 inhibitors in order to delay resistance or provide synergistic effects. Here, we review the use of CDK4/6 inhibitors in prostate cancer and potential combinations based on known resistance mechanisms to CDK4/6 inhibitors, prostate cancer regulatory pathways, and prostate-cancer-specific genomic alterations.
| S-EPMC7576355 | biostudies-literature
Project description:Aberrant androgen receptor (AR) activation is the major driver of castrate resistant prostate cancer (CRPC). CRPC is ultimately fatal and more therapeutic agents are needed to treat this disease. Compounds that target the androgen axis by inhibiting androgen biosynthesis and or AR signaling are potential candidates for use in CRPC treatment and are currently being pursued aggressively. Aldo-keto reductase 1C3 (AKR1C3) plays a pivotal role in androgen biosynthesis within the prostate. It catalyzes the 17-ketoreduction of weak androgen precursors to give testosterone and 5?-dihydrotestosterone. AKR1C3 expression and activity has been implicated in the development of CRPC, making it a rational target. Selective inhibition of AKR1C3 will be important, however, due to the presence of closely related isoforms, AKR1C1 and AKR1C2 that are also involved in androgen inactivation. We examine the evidence that supports the vital role of AKR1C3 in CRPC and recent developments in the discovery of potent and selective AKR1C3 inhibitors. This article is part of a Special Issue entitled 'CSR 2013'.
| S-EPMC3805777 | biostudies-literature
Project description:BackgroundRadium-223 is a bone-targeting radiopharmaceutical that extends survival in mCRPC. Postapproval data are limited, and the value of biochemical and radiologic monitoring during radium therapy is unknown.Patients and methodsWe conducted a retrospective study of 29 patients with mCRPC who received radium-223 at 1 of 3 participating institutions between August 2013 and December 2014. Trend of PSA, radiographic changes, and association of biochemical and clinical variables with PSA trend were measured.ResultsThe median age of patients was 70 years, 79% of patients (N = 23) were European Americans, and 17% of patients (N = 5) were African Americans. Twenty patients (69%) had received at least 3 lines of prior therapies. Some 38% of patients (N = 11) received all 6 cycles of radium-223. Twenty patients (69%) had an increase in PSA during radium therapy, and 4 patients (14%) had a decline in PSA levels. Five patients had visceral metastases on computed tomography imaging performed during the course of radium-223.ConclusionsRadium therapy in mCRPC was associated with an increase in PSA in the majority of these heavily pretreated patients. The development of visceral disease was not uncommon, suggesting a need for follow-up computed tomography monitoring during radium-223 therapy. The significance of early increases in PSA and pain with radium-223 is still uncertain. Although pain and PSA flare have been reported in patients who subsequently have a dramatic response to therapy, we observed that a PSA increase or pain flare correlates to an improvement in bone scans only in a minority of patients.
| S-EPMC6849387 | biostudies-literature
Project description:Abiraterone treats metastatic castrate-resistant prostate cancer by inhibiting CYP17A, an enzyme for testosterone auto-production. With standard dosing, evolution of resistance with treatment failure (radiographic progression) occurs at a median of ~16.5 months. We hypothesize time to progression (TTP) could be increased by integrating evolutionary dynamics into therapy. We developed an evolutionary game theory model using Lotka-Volterra equations with three competing cancer "species": androgen dependent, androgen producing, and androgen independent. Simulations with standard abiraterone dosing demonstrate strong selection for androgen-independent cells and rapid treatment failure. Adaptive therapy, using patient-specific tumor dynamics to inform on/off treatment cycles, suppresses proliferation of androgen-independent cells and lowers cumulative drug dose. In a pilot clinical trial, 10 of 11 patients maintained stable oscillations of tumor burdens; median TTP is at least 27 months with reduced cumulative drug use of 47% of standard dosing. The outcomes show significant improvement over published studies and a contemporaneous population.
| S-EPMC5703947 | biostudies-literature
Project description:BackgroundPembrolizumab is approved for patients with metastatic, microsatellite instability (MSI)-high or mismatch repair-deficient (dMMR) solid tumors. However, very few men with prostate cancer were included in these initial studies.MethodsWe performed a single institution retrospective review of men with metastatic castrate-resistant prostate cancer (mCRPC) who were treated with pembrolizumab. The primary objective was to describe the clinical efficacy of pembrolizumab associated with patient and genomic characteristics.ResultsWe identified 48 men who received ≥1 cycle of pembrolizumab for mCRPC. Of these, 94% (45/48) had ≥3 prior lines of therapy for mCRPC. Somatic tumor sequencing was available in 18/48 men (38%). We found that 17% (8/48) had a ≥50% confirmed PSA decline with pembrolizumab, and 8% (4/48) had a ≥90% PSA decline with durations of response ranging from 3.1 to 16.3 months. Two of these four men had mutations in LRP1b, one of whom also had MSH2 loss and was MSI-H and TMB-high. Despite prior progression on enzalutamide, 48% (23/48) of men were treated with concurrent enzalutamide. The median PSA progression-free-survival was 1.8 months (range 0.4-13.7 months), with 31% of patients remaining on pembrolizumab therapy and 54% of men remain alive with a median follow-up of 7.1 months.ConclusionsIn a heavily pretreated population of men with mCRPC, pembrolizumab was associated with a ≥50% PSA decline in 17% (8/48) of men, including a dramatic ≥90% PSA response in 8% (4/48), two of whom harbored pathogenic LRP1b mutations suggesting that LRP1b mutations may enrich for PD-1 inhibitor responsiveness in prostate cancer.
| S-EPMC6712455 | biostudies-literature
Project description:Ensemble methods have been successfully applied in a wide range of scenarios, including survival analysis. However, most ensemble models for survival analysis consist of models that all optimize the same loss function and do not fully utilize the diversity in available models. We propose heterogeneous survival ensembles that combine several survival models, each optimizing a different loss during training. We evaluated our proposed technique in the context of the Prostate Cancer DREAM Challenge, where the objective was to predict survival of patients with metastatic, castrate-resistant prostate cancer from patient records of four phase III clinical trials. Results demonstrate that a diverse set of survival models were preferred over a single model and that our heterogeneous ensemble of survival models outperformed all competing methods with respect to predicting the exact time of death in the Prostate Cancer DREAM Challenge.
| S-EPMC5500862 | biostudies-literature
Project description:Prostate cancer is a common cancer in men; for metastatic disease, it has a 5-year survival rate of 30%. No FDA-approved therapy for castrate-resistant prostate cancer (CRPC) known to improve survival was available until 2004, when based on a significant survival benefit over mitoxantrone, docetaxel in combination with prednisone was approved. In combination with prednisone, cabazitaxel, which was approved in the United States in 2010, is indicated for patients with metastatic CRPC previously treated with a docetaxel-containing regimen. This case report describes the treatment of a man 58 years of age who was diagnosed with advanced prostate cancer in 2006. He was initially managed with radical prostatectomy followed by androgen deprivation therapy, but a rising prostate-specific antigen (PSA) level led to enrollment in a clinical trial of HE3235 for 6 months. Subsequently, with progression of disease, he was treated with docetaxel for 4 months and then palliative radiation therapy. Cabazitaxel was initiated in October 2010; his condition stabilized within weeks, and he experienced a progressive decline in his PSA level from a peak of 5,424 ng/ml. Continued treatment with cabazitaxel resulted in his being weaned off pain medications and resuming his normal activities. After 16 cycles of cabazitaxel, his PSA declined to 994 ng/ml as of January 2012. He tolerated the cabazitaxel well and occasionally received myeloid growth factors for treatment of neutropenia; otherwise, he experienced only mild diarrhea. This response to cabazitaxel is notable, particularly in light of prior failure of multiple therapies.
| S-EPMC3398088 | biostudies-literature