Metabolic Alterations in Prostate Tumorigenesis

Massimo Loda, MD, Principal Investigator

The Loda laboratory has been focused on understanding the mechanisms responsible for metabolic rewiring in prostate tumorigenesis, with a specific interest in lipid metabolism and its regulation. The ultimate goal is to identify metabolic vulnerabilities that can be targeted therapeutically. Our approach is multidisciplinary, utilizing cell lines, orthotopic tumor xenograft, genetically engineered murine models and human tumors.

We have developed, pioneered and disseminated several techniques in molecular pathology, including multiplexed immunohistochemistry and in situ hybridization, ex vivo human tumor organotypic culture method to investigate antitumoral pharmacological properties that preserves the original cancer microenvironment. The landscape and related functional significance of genomic alterations in prostate cancer is studied in large, international cohorts such as the Prostate TCGA Consortium and the Pan Prostate Cancer Group that Dr. Loda co-leads.
The stroma is recognized as an important contributor in the process of carcinogenesis, and a driver of cancer progression. Experimental models demonstrate that altered stromal cells can induce tumor formation in non-cancerous prostate epithelial cells. It is also clear that the stroma morphologically and functionally changes in the presence of cancer. Despite the overwhelming evidence for the importance of the microenvironment in tumor progression, there is limited knowledge on its cellular composition and on how stromal cells signal to epithelial tumor cells, modifying their functional behavior. The Loda lab aims to construct a precise molecular and morphologic stromal map using laser capture microdissection, single cell RNASeq and multiplex immunofluorescence, in order to gain mechanistic insights as to the interaction between tumor cells and the stromal microenvironment that surrounds it.

Active Projects:

• Pharmacologic inhibition of lipogenesis as therapeutic option for castration resistant prostate cancer
• Lipid Elongation via ELOVL5: A Novel Target for Advanced Prostate Cancer
• Functional atlas of mouse and human prostate cancer mesenchyme
• The role of TMPRSS2_ERG fusions in modulating tumor microenvironment in prostate cancer
• Metabolism rewiring by FASN inhibition alters cancer microenvironment
• The relative contribution of endogenous vs. exogenous lipids in prostate cancer
• Integrative genomics, transcriptomics, metabolomics, and histopathology studies in large prostate cancer cohorts
• Metabolomics of prostate cancer Gleason score in tumor tissue and serum
• Highly multiplexed spatial transcriptomics and proteomics

Active Grants:

• Pharmacologic Inhibition of Lipogenesis Suppresses AR and its Splice Variants to Inhibit Progression of Castration Resistant Prostate Cancer (W81XWH-17-1-0483)
  PI: Massimo Loda, MD
  Role: Initiating PI
  DOD PCRP Impact Award 9/30/17-9/29/22
  

  The specific aims of this project are 1) Determine the role of FASN inhibition on enzalutamide and abiraterone resistance, where resistance is due to AR-Vs expression; 2) Generation of organoids from human PDX models evaluated and characterized in aim 1 and from primary and metastatic human prostate cancer; 3): Mechanism of AR regulation by FASN inhibition.

• Precision Interception of Aggressive Prostate Cancer in African American Men (P20CA233255)
  PI: Massimo Loda, MD
  Role: Core Director, Biospecimen and Biomarker Core (BBC)
  National Institutes of Health/National Cancer Institute 12/1/18-11/30/21
  

  Our grant proposes a “precision interception” approach designed to impede cancer progression at early stages and avoid development of lethal disease in AA PCa cases. We will focus on newly diagnosed or recurrent AA PCa patients, with the goal to develop and implement tools that can “intercept” the development of castrate-resistant or metastatic PCa and death from PCa in AA men. These approaches can thereby reduce PCa-specific disparities in mortality experienced by AA men. This P20 grant is composed of three multidisciplinary research projects and two cores, as well as a developmental research program.

• Lipid Elongation via ELOVL5: A Novel Target for Advanced Prostate Cancer (W81XWH-19-1-0566)
  PI: Massimo Loda, MD
  DOD PCRP Idea Development Award 9/30/19 – 9/29/22
  

  Our proposal seeks to demonstate that ELOVL5 activity is critical to PCa progression by retuning the properties of cellular membranes, and is an exploitable new target for Castration Resistant Prostate Cancer (CRPC).

Completed Research Support (selected from various over the past three years)

• DF/HCC SPORE in Prostate Cancer (P50CA90381)
  PI: Massimo Loda, MD
  National Institutes of Health/National Cancer Institute 7/1/13-6/30/19

  This SPORE is focused on several important themes in prostate cancer: 1) the identification of lethal prostate cancer using genetic and genomic approaches and 2) understanding the role of metabolism on the development of lethal prostate cancer, and understanding the mechanism of primary and secondary resistance to hormonal therapy and finally elucidating new targets for therapy in men with advanced disease. 

• Molecular Link between Metabolic Syndrome and Prostate Cancer (R01CA131945)
  PI: Massimo Loda, MD
  National Institutes of Health/National Cancer Institute 12/1/07-7/31/19

  We hypothesize that PCa arising in patients with MetS is characterized by a unique molecular phenotype driven by the inactivation of AMPK in prostate tumors cells.

• Targeting the p110beta isoform of P13 kinase in prostate cancer (R01CA187918)
  PI: Massimo Loda, MD
  National Institutes of Health/National Cancer Institute 4/1/15-3/31/20

  In this grant, we propose to evaluate the therapeutic potential of a novel class of inhibitors in prostate cancer in vitro and in vivo using human cancer cell lines, genetic mouse models as well as primary human prostate tumor explants, to develop biomarkers predictive of response to p110ß inhibition, and to identify optimal combination partner agents for p110ß-based therapy. The studies proposed in this grant will likely provide important information that will help to optimize the clinical impact of this class of inhibitors in PTEN-deficient tumors.