Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors have shown therapeutic success for patients with metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination ...repair (HRR) deficiency.
Preclinical data suggest that PARP inhibitors may have efficacy in a wider population if combined with androgen receptor inhibition.
One phase 2 trial for late-stage mCRPC supports this notion, finding that olaparib added to abiraterone/prednisone improved radiographic progression-free survival (PFS) versus abiraterone/prednisone alone in a population that was not biomarker preselected.
However, another trial with abiraterone and veliparib did not show benefit.
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The PI3K-AKT pathway has pleiotropic effects, and its inhibition has long been of interest in the management of prostate cancer, where a compensatory increase in PI3K signaling has been reported ...following Androgen Receptor (AR) blockade. Prostate cancer cells can also bypass AR blockade through induction of other hormone receptors, in particular the glucocorticoid receptor (GR). Here we demonstrate that AKT inhibition significantly decreases cell proliferation through both cytostatic and cytotoxic effects. The cytotoxic effect is enhanced by AR inhibition and is most pronounced in models that induce compensatory GR expression. AKT inhibition increases canonical AR activity and remodels the chromatin landscape, decreasing enhancer interaction at the GR gene (NR3C1) locus. Importantly, it blocks induction of GR expression and activity following AR blockade. This is confirmed in multiple in vivo models, where AKT inhibition of established xenografts leads to increased canonical AR activity, decreased GR expression, and marked anti-tumor activity. Overall, our results demonstrate that inhibition of the PI3K/AKT pathway can block GR activity and overcome GR-mediated resistance to AR-targeted therapy. Ipatasertib is currently in clinical development, and GR induction may be a biomarker to identify responsive patients or a responsive disease state.
Ephrin receptors and their membrane-localized ligands induce bidirectional signaling and facilitate tumor-stroma interactions. Blocking the EphB4-EphrinB2 pathway, which can be accomplished by ...soluble EphB4 conjugated to human serum albumin (sEphB4-HSA), promotes cell death in preclinical models of aggressive prostate cancer. We hypothesized that targeting the EphB4-EphrinB2 pathway may serve as a therapeutic target in the treatment of metastatic castration resistant prostate cancer (mCRPC).
We conducted a single arm, phase II trial in patients with progressive mCRPC who had received no more than 3 prior therapies for mCRPC. sEphB4-HSA 1000 mg IV was administered every 2 weeks, extending to 3 weeks starting from cycle 7. The primary endpoint was confirmed prostate specific antigen (PSA) response rate. We employed a Simon 2-stage Minimax design with 15 patients in the first stage and 10 additional patients in the second stage.
Fourteen eligible patients enrolled in the study with median age of 73.5 years (range: 52-83) and median baseline PSA of 65.11 ng/mL (range: 7.77-2850 ng/mL). Most patients received 3 prior therapies for mCRPC. The median treatment duration with sEphB4-HSA was 6.5 weeks (range: 2-35 weeks). Three patients experienced a serious adverse event potentially related to therapy, including 1 patient with a grade 5 event (cerebral vascular accident) possibly related to the study drug. No patient had a confirmed PSA response, and the study was stopped for futility. Thirteen patients had PSA progression. The median time to PSA progression was 28 days (90% CI: 28-42 days), and median time to radiologic progression was 55 days (90% CI: 54-72 days). Of 3 patients with measurable disease, 2 had stable disease and one had progressive disease.
In patients with mCRPC who progressed on prior second generation AR-targeted therapy, sEphB4-HSA monotherapy had no discernable anti-tumor activity.
Blocking the EphB4-EphrinB2 pathway has efficacy in preclinical models of prostate cancer. We conducted a single arm trial using sEphB4-HSA in patients with advanced prostate cancer using a Simon 2-stage design. Fourteen patients enrolled in the study. No patient had a confirmed response, and the study was stopped for futility. sEphB4-HSA monotherapy had no anti-tumor activity in patients with mCRPC.
For high-risk prostate cancer, standard treatment options include radical prostatectomy (RP) or radiotherapy plus androgen deprivation therapy (ADT). Despite definitive therapy, many patients will ...have disease recurrence. Imaging has the potential to better define characteristics of response and resistance. In this study, we evaluated prostate multiparametric MRI (mpMRI) before and after neoadjuvant enzalutamide plus ADT.
Men with localized intermediate- or high-risk prostate cancer underwent a baseline mpMRI and mpMRI-targeted biopsy followed by a second mpMRI after 6 months of enzalutamide and ADT prior to RP. Specimens were sectioned in the same plane as mpMRI using patient-specific 3D-printed molds to permit mpMRI-targeted biopsies to be compared with the same lesion from the RP. Specimens were analyzed for imaging and histologic correlates of response.
Of 39 patients enrolled, 36 completed imaging and RP. Most patients (92%) had high-risk disease. Fifty-eight lesions were detected on baseline mpMRI, of which 40 (69%) remained measurable at 6-month follow-up imaging. Fifty-five of 59 lesions (93%) demonstrated >50% volume reduction on posttreatment mpMRI. Three of 59 lesions (5%) demonstrated growth in size at follow-up imaging, with two lesions increasing more than 3-fold in volume. On whole-mount pathology, 15 patients demonstrated minimal residual disease (MRD) of <0.05 cc or pathologic complete response. Low initial mpMRI relative tumor burden was most predictive of MRD on final pathology.
Low relative lesion volume at baseline mpMRI was predictive of pathologic response. A subset of patients had limited response. Selection of patients based on these metrics may improve outcomes in high-risk disease.
Chemotherapeutic agents induce apoptosis in cancer cells through effects on multiple intracellular targets. Recent observations
suggest that a consistent cellular response to chemotherapeutic agents ...of disparate classes is down-regulation of glycolytic
metabolism. Inhibition of glycolytic activity has been linked to apoptotic induction in several models. The serine/threonine
kinase Akt (protein kinase B) promotes both glycolytic metabolism and survival, and these functions have been shown to be
linked. Because of its key role in both glycolysis and survival, we examined the function of Akt in the cellular response
to cytotoxic agents. Following exposure to any of several chemotherapeutic agents, an initial up-regulation in endogenous
Akt activity is rapidly suppressed. Using cells containing constitutively active myristoylated Akt, dominant-negative kinase-dead
Akt, or an empty vector control, we show here that Akt activation markedly increases resistance to microtubule-directed agents,
including vincristine, colchicine, and paclitaxel. Akt also maintains increased glycolytic rate in response to antimicrotubule
treatment. Rapamycin inhibits Akt-mediated maintenance of glycolysis and therapeutic resistance, indicating that these effects
are dependent on mammalian target of rapamycin (mTOR). Furthermore, an activated mTOR mutant confers resistance to antimicrotubule
agents. Taken together, these observations suggest that activation of the Akt-mTOR signaling pathway can augment glucose utilization
and promote resistance to chemotherapeutic agents that do not directly target metabolic regulation. These data provide insight
into potentially synergistic combinations of anticancer therapies.
Solid tumors harboring BRCA1 or BRCA2 mutations have been shown to respond to PARP inhibitors. These responses are partial and transient. In this case report, we describe an 82-year-old male with ...poorly differentiated prostate cancer with metastases to the lung, liver, abdomen, and bowel. Molecular testing demonstrated alterations in BRCA2, ERG, and TP53. Based on this result, he was enrolled in a therapeutic trial and received carboplatin, gemcitabine, and veliparib, to which he had a partial response. He continued to respond while on veliparib maintenance alone, and after 38 cycles he had a sustained complete response. A sustained complete response to PARP inhibitor-based therapy has not previously been described for prostate cancer. This case suggests that cytotoxic therapy in combination with PARP inhibitors may yield exceptional responses, and molecular studies may help guide patient selection for these therapies.
Randomized trials serve as the standard for comparative studies of treatment effects. In many settings, it may not be feasible or ethical to conduct a randomized study, and researchers may pursue ...observational studies to better understand clinical outcomes. A central limitation of observational studies is the potential for confounding bias that arises because treatment assignment is not random. Thus, the observed associations may be attributable to differences other than the treatment being investigated and causality cannot be assumed.
Objective To compare pathological characteristics, treatment patterns, and survival in patients with ductal adenocarcinoma (DC) compared to those with acinar adenocarcinoma (AC). Materials and ...Methods Using the National Cancer Database, we identified patients diagnosed with clinically localized (cN0, cM0) pure DC (n = 1328) and AC (n = 751,635) between 1998 and 2011. High-risk AC was defined as Gleason 8-10. Demographic, treatment, pathological, and survival characteristics of patients were compared. Results Compared to patients with Gleason 8-10 AC, those with DC presented with lower mean prostate-specific antigen (10.3 vs 16.2 ng/mL, P <.001), had similar rates (11.7% vs 11.5%, P = .8) of clinical extra-capsular extension (stage ≥ cT3), and were more likely to undergo prostatectomy (54% vs 36%, P <.001). Compared to patients with Gleason 8-10 AC undergoing prostatectomy, those with DC had more favorable pathology: stage ≥ T3 (39% vs 52%, P <.001), fewer positive lymph nodes (4% vs 11%, P <.001), and fewer positive margins (25% vs 33%, P <.001). On Kaplan-Meier analysis, patients with DC had similar 5-year survival (75.0%, 95% confidence interval CI 71.7-78.9) compared to those with Gleason 8-10 AC (77.1%, 95% CI 76.6%-77.6%, P = .2). On Cox multivariable analysis, patients with Gleason 8-10 AC had a similar risk of death compared to those with DC (hazards ratio = 0.92, 95% CI 0.69-1.23, P = 6). Conclusion In this large contemporary population-based series, patients with DC of the prostate presented with lower prostate-specific antigen, had more favorable pathological features, and similar overall survival compared to men with Gleason 8-10 AC.
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