Research

The Loda Laboratory is broadly focused on identifying the causes and drivers of prostate cancer through the study of cellular metabolism and cell cycle control. Our approach to research originates from unresolved pathogenetic mechanisms of disease and extends to explore at the “clinical” level an unproven assumption.  If there is reason to believe that a given theory may have an impact on clinical care, we take back to the lab the specific biological problem and attempt to solve it at the bench.  The hope being to eventually bring it back to the clinical arena, this time with a proven mechanism and hopefully with potential novel therapeutic avenues to explore.

Specifically, the Loda Lab seeks to determine the molecular underpinnings that link metabolic syndrome and biologically aggressive prostate cancer. Dr. Loda is a molecular pathologist by training, and has assembled a multidisciplinary team of molecular and cell biologists, molecular genetic epidemiologists, metabolomics experts, in vivo imagers and bioinformaticists to study metabolic alterations in prostate cancer. We interrogate cell lines for biochemical questions, but also use genetically engineered mouse models and apply bioinformatically-generated signatures to large cohorts of human databases. Our team has recently developed a method to perform metabolic profiling in formalin-fixed, paraffin embedded tissue. We also utilize ex vivo organotypic cultures of human prostate cancers to test their response to inhibitors of lipogenesis.

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Metabolism and prostate cancer

Genetic alterations in cancer define specific metabolic pathways that support their survival and growth. Thus, simultaneous targeting of selected metabolic enzymes and “driving” oncogenes may be cancer cell-selective. We discovered that USP2a stabilizes fatty acid synthase (FASN) by preventing its degradation and showed that FASN is a metabolic oncogene. This was the first report of a metabolic oncogene in prostate cancer. Significant interactions between body mass index, FASN polymorphisms and FASN expression suggest FASN as a potential link between obesity and poor prostate cancer outcome, raising the possibility that FASN inhibition could reduce PCa-specific mortality, particularly in overweight men. We found that the energy sensor AMPK, a master regulator of metabolism, represents an ideal target in prostate cancer. Fatty acid synthesis is required at the G2/M, represents a novel “lipogenic checkpoint” and may be therapeutically exploited with FASN inhibitors or AMPK activators. We have developed a method to perform metabolic profiling in formalin-fixed, paraffin embedded tissue.

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Role of de-ubiquitinating enzymes in prostate cancer

Dr. Loda’s first RO1 aimed at the identification of de-ubiquitinating enzymes expressed in prostate cancer and their targets. As mentioned above, we discovered that USP2a binds to and stabilizes fatty acid synthase (FASN) by preventing its degradation. We demonstrated that USP2a behaves as an oncogene in prostate cancer and that it enhances c-Myc expression via the modulation of specific subsets of microRNAs. We discovered that USP2a localizes to early endosomes antagonizing EGFR endocytosis. This could be exploited therapeutically in cancers over-expressing EGFR

Cell cycle regulation in cancer

We have been interested in the dissection of the pathways leading to altered cell cycle regulation in human solid tumors. We were the first to discover a tumor-specific proteolytic mechanism targeting p27 in colon tumors and establishing the loss of this cyclin-dependent kinase inhibitor as a powerful prognostic maker in many human cancers. More recently, we discovered a novel metabolic (“lipogenic”) G2/M checkpoint that can be exploited therapeutically. We showed that the inhibition of fatty acid synthesis arrested the cells at G2/M despite the presence of abundant fatty acids in the media. Our results suggest that de novo lipogenesis is essential for cell cycle completion.

Methods in molecular pathology to classify prostate cancer

We have developed, pioneered and disseminated several techniques in molecular pathology including multiplexed immunohistochemistry and in situ hybridization, de-convolution by spectral imaging and subsequent bioinformatics analysis, ex vivo tumor organotypic culture method to investigate antitumoral pharmacological properties that preserves the original cancer microenvironment, to the discovery of p63 as a diagnostic marker used in prostate cancer diagnosis, to the landscape of genomic alterations in prostate cancer as a co-leader of the Prostate TCGA Consortium and the molecular landscape of tumor stroma in prostate cancer

In collaboration with colleagues at both DFCI and the Harvard T.H. Chan School of Public Health, the Loda Lab is at the forefront of molecular pathology in prostate cancer. Through the study of human tumors, transgenic mice, cell lines, and genomics, our overarching aim is to identify the key mediators of prostate cancer.