Massimo Loda

Metabolism and prostate cancer. Genetic alterations in cancer define specific metabolic pathways that support their survival and growth. The central hypothesis driving research efforts in the Loda lab is that simultaneous targeting of rate limiting metabolic enzymes together with “driving” oncogenes that determine metabolic re-wiring, is cancer cell-specific and may result in synthetic lethality. 

In many papers over several years, we discovered significant interactions between body mass index, FASN genetic polymorphisms and high unsaturated fat diet with prostate cancer, suggesting that systemic alterations in lipid metabolism contribute to poor prostate cancer outcome. While exogenous lipids contribute to the pathogenesis of prostate cancer, maintenance and progression depend mainly on enhanced endogenous synthesis, centered on the highly upregulated rate limiting enzyme fatty acid synthase (FASN). 

We discovered that the de-ubiquitinating enzyme USP2a stabilizes FASN by preventing its degradation and formally demonstrated that FASN is a “metabolic oncogene” in prostate cancer. Investigating ties between cell cycle control and metabolism, we showed that endogenous synthesis of fatty acids is required at the G2/M transition and represents a novel “lipogenic checkpoint”. Inhibition of de novo lipogenesis by genetic or pharmacologic means in prostate cancer cells results in increase in reactive oxygen species due to peroxidation of polyunsaturated fatty acids taken up from the microenvironment to compensate endogenous inhibition. 

Importantly, downregulation of both the androgen receptor and its ligand-independent splice variants occurs as a result of FASN inhibition. Subsequently, cancer cells can undergo cell cycle arrest, apoptosis or ferroptosis. We reasoned that both the energy sensor AMPK, a master regulator of metabolism and lipogenesis, and FASN, the rate-limiting enzyme for de novo lipogenesis, represent ideal targets in prostate cancer. This may be therapeutically exploited with FASN inhibitors or AMPK activators. Inhibition of lipogenesis is actively being exploited therapeutically. 

We designed and recently opened a Phase I, FASN inhibitor (TVB-2640) Administered in Combination with Enzalutamide in Men with Metastatic Castration-Resistant Prostate Cancer (mCRPC). This is the first clinical trial to evaluate a new approach to treating metastatic, castration-resistant prostate cancer by targeting the AR pathway through inhibition of lipid synthesis. (ClinicalTrials.gov ID NCT05743621). 

Role of the stromal microenvironment in prostate cancer progression. While progression from normal prostatic epithelium to invasive cancer is driven by molecular alterations, tumor cells and cells in the cancer microenvironment are co-dependent and co-evolve. We hypothesize that stromal cells surrounding prostate cancer, are transcriptionally and metabolically rewired to affect prostate cancer progression. 

We discovered that crossing knockout (KO) mice for FASN with the PTEN KO model of prostate cancer, massively reduced the stromal reaction and the invasive potential of the tumors in these genetically engineered mice (GEMMs). We therefore investigated in detail stromal cell populations. Our group described that stromal transcriptional programs vary in areas surrounding low vs. high grade human prostate cancer. 

In addition, benign stroma was transcriptionally distinct in tumor compared to non-tumor-bearing specimens. Furthermore, a stromal gene signature enriched in bone remodeling and immune-related pathways predicted metastases. We therefore analyzed mesenchymal cells from GEMMs of prostate cancer representing different stages of the disease by single-cell RNA sequencing (scRNA-seq) and compared them to human tumors. 

We identified distinct stromal populations that are conserved between mouse models and human prostate cancers driven by the same genomic alterations. Importantly, the transcriptional profiles of the stroma of murine models of advanced disease were similar to those of human prostate cancer bone metastases. Our lab is currently studying the molecular and metabolic characteristics of stromal cells to dissect the mechanism through which mesenchymal cells affect prostate cancer progression and the metastatic process.