The majority of kidney cancers are detected incidentally and typically diagnosed at a localized stage, however, the development of regional or distant disease occurs in one-third of patients. Over ...90% of kidney tumors are renal cell carcinomas, of which, clear cell is the most predominate histologic subtype. Von Hippel Lindau (VHL) gene alterations result in the overexpression of growth factors that are central to the pathogenesis of clear cell carcinoma. The therapeutic strategies have revolved around this tumor suppressor gene and have led to the approval of tyrosine kinase inhibitors (TKI) targeting the vascular endothelial growth factor (VEGF) axis. The treatment paradigm shifted with the introduction of immune checkpoint inhibitors (ICI) and programed death-1 (PD-1) inhibition, leading to durable response rates and improved survival. Combinations of TKI and/or ICIs have become the standard of care for advanced clear cell renal cell carcinoma (ccRCC), changing the outlook for patients, with several new and promising therapeutic targets under development.
The recent approval of 177Lu PSMA-617 (Pluvicto®) by the United States Food and Drug Administration (FDA) is the culmination of decades of work in advancing the field of targeted radionuclide therapy ...for metastatic prostate cancer. 177Lu PSMA-617, along with the bone specific radiotherapeutic agent, 223RaCl2 (Xofigo®), are now commonly used in routine clinical care as a tertiary line of therapy for men with metastatic castrate resistant prostate cancer and for osseus metastatic disease respectively. While these radiopharmaceuticals are changing how metastatic prostate cancer is classified and treated, there is relatively little guidance to the practitioner and patient as to how best utilize these therapies, especially in conjunction with other more well-established regimens including hormonal, immunologic, and chemotherapeutic agents. This review article will go into detail about the mechanism and effectiveness of these radiopharmaceuticals and less well-known classes of targeted radionuclide radiopharmaceuticals including alpha emitting prostate specific membrane antigen (PSMA)-, gastrin-releasing peptide receptor (GRPR)-, and somatostatin targeted radionuclide therapeutics. Additionally, a thorough discussion of the clinical approach of these agents is included and required futures studies.
Bromodomains (BD) are epigenetic readers of histone acetylation involved in chromatin remodeling and transcriptional regulation of several genes including protooncogene cellular myelocytomatosis ...(c-Myc). c-Myc is difficult to target directly by agents due to its disordered alpha helical protein structure and predominant nuclear localization. The epigenetic targeting of c-Myc by BD inhibitors is an attractive therapeutic strategy for prostate cancer (PC) associated with increased c-Myc upregulation with advancing disease. MT-1 is a bivalent BD inhibitor that is 100-fold more potent than the first-in-class BD inhibitor JQ1. MT-1 decreased cell viability and causes cell cycle arrest in G0/G1 phase in castration-sensitive and resistant PC cell lines in a dose-dependent fashion. The inhibition of c-Myc function by MT-1 was molecularly corroborated by the de-repression of Protein Kinase D1 (PrKD) and increased phosphorylation of PrKD substrate proteins: threonine 120, serine 11, and serine 216 amino acid residues in β-Catenin, snail, and cell division cycle 25c (CDC25c) proteins, respectively. The treatment of 3D cell cultures derived from three unique clinically annotated heavily pretreated patient-derived PC xenografts (PDX) mice models with increasing doses of MT-1 demonstrated the lowest IC
in tumors with c-Myc amplification and clinically resistant to Docetaxel, Cabazitaxel, Abiraterone, and Enzalutamide. An intraperitoneal injection of either MT-1 or in combination with 3jc48-3, an inhibitor of obligate heterodimerization with MYC-associated protein X (MAX), in mice implanted with orthotopic PC PDX, decreased tumor growth. This is the first pre-clinical study demonstrating potential utility of MT-1 in the treatment of PC with c-Myc dysregulation.
Background
The objective of this study was to evaluate the efficacy of gemcitabine plus nab‐paclitaxel in patients with recurrent ovarian cancer.
Methods
We performed a single institution ...retrospective review of patients with recurrent ovarian cancer who were treated with gemcitabine plus nab‐paclitaxel from 2012 to 2018 at the Mayo Clinic in Florida.
Results
Twenty patients were identified and the median PFS for patients treated with gemcitabine plus nab‐paclitaxel was 9 months (95% CI, 5.7–20.7). Overall, 17 of the 20 patients (85%) achieved a clinical benefit (complete response 5%, partial response 55%, or stable disease at 3 months 25%). For platinum‐sensitive disease and platinum‐resistant disease, the median OS were 38.7 months (95% CI, 5.8–63.1) and 31.2 months (95% CI, 12.8–51.8), respectively (p = 0.4306).
Conclusion
This well‐tolerated regimen shows promising activity in recurrent ovarian cancer and is a viable option for patients who are intolerant to paclitaxel or carboplatin because of allergic reactions.
In this retrospective review, 20 patients were treated with gemcitabine plus nab‐paclitaxel and the median PFS was 9 months (95% CI, 5.7–20.7). Overall, 17 of the 20 patients (85%) achieved a clinical benefit (complete response 5%, partial response 55%, or stable disease at 3 months 25%). For platinum‐sensitive disease and platinum‐resistant disease, the median OS were 38.7 months (95% CI, 5.8–63.1) and 31.2 months (95% CI, 12.8–51.8), respectively (p = 0.4306). This regimen is a viable and well tolerated option for patients who are intolerant to paclitaxel or carboplatin because of allergic reactions.
Conventional imaging has been the standard imaging modality for assessing prostate cancer recurrence and is utilized to determine treatment response to therapy. Molecular imaging with PSMA PET-CT has ...proven to be more accurate, sensitive, and specific at identifying pelvic or distant metastatic disease, resulting in earlier diagnosis of advanced disease. Since advanced disease may not be seen on conventional imaging, due to its lower sensitivity, but can be identified by molecular imaging, this reveals that metastatic prostate cancer occurs on a continuum from negative PSMA PET-CT and negative conventional imaging to positive PSMA PET-CT and positive conventional imaging. Understanding this continuum, the accuracy of these modalities, and treatment related outcomes based on imaging, will allow the clinician to counsel patients on management. This review will highlight the differences in conventional and molecular imaging in prostate cancer and how PSMA PET-CT can be used for the management of prostate cancer patients in different clinical scenarios, while providing cautionary notes for overtreatment.
Metastatic castration-resistant prostate cancer (mCRPC) is an aggressive malignancy with poor outcomes. To investigate novel therapeutic strategies, we characterized three new metastatic prostate ...cancer PDTX models and developed 3D spheroids from each to investigate molecular targeted therapy combinations including CDK4/6 inhibitors (CDK4/6i) with AKT inhibitors (ATKi). Metastatic prostate cancer tissue was collected and three PDTX models were established and characterized using WES. PDTX 3-D spheroids were developed from these three PDTXs to show resistance patterns and test novel molecular targeted therapies. CDK4/6i's were combined with AKTi's to assess synergistic antitumor response to prove our hypothesis that blockade of AKT overcomes drug resistance to CDK4/6 inhibitor. This combination was evaluated in PDTX 3-D spheroids and in vivo experiments with responses measured by tumor volumes, PSA and Ga-68 PSMA-11 PET-CT imaging. We demonstrated CDK4/6i's with AKTi's possess synergistic antitumor activity in three mCRPC PDTX models. These models have multiple unique pathogenic and deleterious genomic alterations with resistance to single agent CDK4/6i's. Despite this, combination therapy with AKTi's was able to overcome resistance mechanisms. The IHC and Western blot analysis confirmed on target effects, while tumor volume, serum PSA ELISA, and radionuclide imaging demonstrated response to therapy with statistically significant SUV differences seen with Ga-68 PSMA-11 PET-CT. These preclinical data demonstrating antitumor synergy by overcoming single agent CDK 4/6i as well as AKTi drug resistance provide the rational for a clinical trial combining a CDK4/6i with an AKTi in mCRPC patients whose tumor expresses wild type RB1.
•Lung-only metastatic prostate cancer represents a good prognostic caracteristic.•ADT with or without surgery can induce a complete response in patients with lung-only metastatic prostate ...cancer.•Patient's with lung-only metastatic prostate cancer can achieve a complete response after progression on ADT with the addition of abiraterone.
Lung-only metastatic prostate cancer can be seen in 4.6% of patients and historically patients with visceral metastastic disease are considered high risk. In order to determine survival outcomes in this patient population, we conducted a restrospective review of patients with metastatic hormone sensitive prostate cancer with lung-only metastases. In this single institution review, 10 patients were identified with 8 achieving a complete response and 2 achieving a partial response when treated with androgen deprevation therapy (ADT) with or without metastastetomy. The median progression free survival was 64.4 months with 8 of these patients (80%) with ongoing complete response at time of follow-up. Lung-only metastases may serve as a good prognostic characteristic which will allow the clinician to treat with ADT alone with or without surgery to minimize treatment realted toxicity and still offer the ability to achieve a complete response with prolonged survival.
The efficacy of pembrolizumab monotherapy in metastatic castration-resistant prostate cancer patients (mCRPC) when stratified by MSI-H and/or TMB-H is poorly defined. Additionally, outcomes based on ...sequencing source (i.e., tissue or liquid biopsy) have not been well described. We sought to assess outcomes of pembrolizumab monotherapy in patients with mCRPC and compare efficacy based on MSI-H and/or TMB-H when identified by tissue or liquid biopsy.
A retrospective analysis was performed of mCRPC patients treated at Mayo Clinic with pembrolizumab monotherapy between 2018 and 2023. Objective response rates (ORR), median progression-free survival (mPFS), and overall survival (mOS), were determined by RECIST v1.1 criteria.
Twenty-two patients with mCRPC received pembrolizumab monotherapy for at least 3 cycles for a MSI-H or TMB-H indication. All patients had next generation sequencing (NGS) performed via tissue (n = 11) or liquid (n = 10) biopsy source. The ORR was 50% (27.3% complete response and 22.7% had partial response). The mPFS for TMB 10-14.9 mut/Mb (n = 4), TMB 15-24.9 mut/Mb (n = 6), and TMB ≥ 25 mut/Mb (n = 10) was 2.1, not reached (NR), and NR, respectively (p = 0.0003). The mOS for these same groups was 5.1 months, 20.5 months, and not reached, respectively. Among patients with TMB-H without co-occurring MSI-H or CDK12 (n = 6), none experienced a response and only one patient had stable disease compared to patients with MSI-H (n = 12) for whom the ORR was 75%. Immunotherapy responsive alterations such as ATRX and PTCH1 mutations were frequently noticed among patients who had complete response (CR).
Our hypothesis-generating study suggests that MSI-H drives the efficacy of pembrolizumab in mCRPC with better survival outcomes as TMB increases. Clinicians should consider alternative treatment strategies for advanced prostate cancer when TMB-H is present without co-occurring MSI-H or CDK12.
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.
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