Management of Advanced Prostate Cancer in the Precision Oncology Era.

Prostate cancer (PC) is the second leading cause of cancer death in men in the United States. While diversified and improved treatment options for aggressive PC have improved patient outcomes, metastatic castration-resistant prostate cancer (mCRPC) remains incurable and an area of investigative therapeutic interest. This review will cover the seminal clinical data supporting the indication of new precision oncology-based therapeutics and explore their limitations, present utility, and potential in the treatment of PC. Systemic therapies for high-risk and advanced PC have experienced significant development over the past ten years. Biomarker-driven therapies have brought the field closer to the goal of being able to implement precision oncology therapy for every patient. The tumor agnostic approval of pembrolizumab (a PD-1 inhibitor) marked an important advancement in this direction. There are also several PARP inhibitors indicated for patients with DNA damage repair deficiencies. Additionally, theranostic agents for both imaging and treatment have further revolutionized the treatment landscape for PC and represent another advancement in precision medicine. Radiolabeled prostate-specific membrane antigen (PSMA) PET/CT is rapidly becoming a standard of care for diagnosis, and PSMA-targeted radioligand therapies have gained recent FDA approval for metastatic prostate cancer. These advances in precision-based oncology are detailed in this review.

MAP3K7 Loss Drives Enhanced Androgen Signaling and Independently Confers Risk of Recurrence in Prostate Cancer with Joint Loss of CHD1.

Prostate cancer genomic subtypes that stratify aggressive disease and inform treatment decisions at the primary stage are currently limited. Previously, we functionally validated an aggressive subtype present in 15% of prostate cancer characterized by dual deletion of MAP3K7 and CHD1. Recent studies in the field have focused on deletion of CHD1 and its role in androgen receptor (AR) chromatin distribution and resistance to AR-targeted therapy; however, CHD1 is rarely lost without codeletion of MAP3K7. Here, we show that in the clinically relevant context of co-loss of MAP3K7 and CHD1 there are significant, collective changes to aspects of AR signaling. Although CHD1 loss mainly impacts the expansion of the AR cistrome, loss of MAP3K7 drives increased AR target gene expression. Prostate cancer cell line models engineered to cosuppress MAP3K7 and CHD1 also demonstrated increased AR-v7 expression and resistance to the AR-targeting drug enzalutamide. Furthermore, we determined that low protein expression of both genes is significantly associated with biochemical recurrence (BCR) in a clinical cohort of radical prostatectomy specimens. Low MAP3K7 expression, however, was the strongest independent predictor for risk of BCR over all other tested clinicopathologic factors including CHD1 expression. Collectively, these findings illustrate the importance of MAP3K7 loss in a molecular subtype of prostate cancer that poses challenges to conventional therapeutic approaches. IMPLICATIONS: These findings strongly implicate MAP3K7 loss as a biomarker for aggressive prostate cancer with significant risk for recurrence that poses challenges for conventional androgen receptor-targeted therapies.

Balancing energy expenditure and storage with growth and biosynthesis during Drosophila development.

Sustaining life requires efficient uptake of nutrients and conversion to useable forms. Almost everything about this process is dynamic. Nutrient availability fluctuates and changing environmental conditions impose new demands that can tip the metabolic equilibrium from biosynthesis and macromolecule storage to energy expenditure. At the same time, the organism itself changes, particularly during the rapid growth and differentiation in early development and also later in life as the adult ages. Here we review what has been learned from Drosophila melanogaster as an experimental model about the connections between external signals, signaling pathways, tissues and organs that allow animals to balance energy storage with expenditure in the face of change, both intrinsic and extrinsic.

Gene-Diet Interactions: Dietary Rescue of Metabolic Effects in spen-Depleted Drosophila melanogaster.

Obesity and its comorbidities are a growing health epidemic. Interactions between genetic background, the environment, and behavior (i.e., diet) greatly influence organismal energy balance. Previously, we described obesogenic mutations in the gene Split ends (Spen) in Drosophila melanogaster, and roles for Spen in fat storage and metabolic state. Lipid catabolism is impaired in Spen-deficient fat storage cells, accompanied by a compensatory increase in glycolytic flux and protein catabolism. Here, we investigate gene-diet interactions to determine if diets supplemented with specific macronutrients can rescue metabolic dysfunction in Spen-depleted animals. We show that a high-yeast diet partially rescues adiposity and developmental defects. High sugar partially improves developmental timing as well as longevity of mated females. Gene-diet interactions were heavily influenced by developmental-stage-specific organismal needs: extra yeast provides benefits early in development (larval stages) but becomes detrimental in adulthood. High sugar confers benefits to Spen-depleted animals at both larval and adult stages, with the caveat of increased adiposity. A high-fat diet is detrimental according to all tested criteria, regardless of genotype. Whereas Spen depletion influenced phenotypic responses to supplemented diets, diet was the dominant factor in directing the whole-organism steady-state metabolome. Obesity is a complex disease of genetic, environmental, and behavioral inputs. Our results show that diet customization can ameliorate metabolic dysfunction underpinned by a genetic factor.

Stored Lipids: More Than Mere Fuel.

Stored lipids fuel early development, but with adulthood comes changing metabolic needs. In this issue of Developmental Cell, Storelli et al. (2018) show that the Drosophila HNF4 nuclear receptor drives adults to convert lipids to very long chain fatty acids and hydrocarbons for an anti-dehydration function likely conserved in mice.