Research projects - Experimental Therapeutics Lab
Metabolic and epigenetic drivers of treatment resistance in cancer
Epigenetic and metabolic processes have fundamental roles in transcriptional and phenotypic reprogramming in cancer. These processes affect the rare population of stem-like tumor cells capable of self-renewal and continuous expansion and are instrumental in sustaining tumor progression, metastatic spread, and disease recurrence. Our data indicate that mitochondrial dynamics and metabolism are essential for preventing senescence and loss of self-renewal of cancer stem cells. Correct execution of mitochondrial division ensures the partitioning of functional mitochondria between stem and non-stem cells in asymmetric cell division. Our data also suggest that mitochondria generate intracellular signals that can either promote or suppress the survival and proliferative capacity of the cancer stem cell progeny. Our objective is to understand the relationship between cancer stem cell biology, mitochondria dynamics, cell metabolism, and epigenetic regulatory mechanisms.
Mitochondrial dynamics at the crossroad between stemness and treatment resistance in prostate cancer
Prostate cancer is one of the most common malignancies and a leading cause of cancer-related deaths in men worldwide. Locally advanced and metastatic prostate cancer is still a critical unmet need. Due to the limited efficacy of the current treatment, it is imperative to expand the horizon of the therapeutic options for advanced prostate cancer. Several lines of evidence indicate that tumor cells capable of self-renewal and continuous expansion sustain tumor progression and treatment failures. Mitochondrial reprogramming and metabolic plasticity are critical features for preserving the long-term survival of CSCs. Mitochondria homeostasis relies on the delicate balance between mitochondrial biogenesis, dynamics, and clearance. We have recently shown that mitochondrial dynamics is essential for partitioning healthy mitochondria between daughter cells and preventing loss of self-renewal in cancer stem cells. Thus, proteins involved in the mitochondrial dynamics machinery are promising targets for developing novel CSC-directed therapies. However, there is still limited information on the mechanisms leading to enhanced mitochondrial dynamics in prostate cancer and the functional consequences of inhibiting these processes. Our studies intend to fill this knowledge gap and provide relevant information on the role of mitochondria in prostate cancer and the basis for developing innovative CSC-directed therapies.
Targeting metabolic reprogramming and plasticity in cancer stem cells to impact tumor progression and treatment resistance
There is increasing interest in the biological pathways that determine the ability of cancer stem cells to adapt to and survive micro-environmental stress and that sustain their tumor-initiating and metastatic properties. A better understanding of these pathways may lead to identifying critical nodes and targetable elements for developing novel strategies for cancer treatment by targeting the tumor-initiating stem-like cancer cells in human tumors. The σ1 receptor is a ligand-activated molecular chaperone localized preferentially at the endoplasmic reticulum (ER) and the mitochondria-associated ER membrane (MAM) domains. Our data suggest that the σ1 receptor has an essential role in tumorigenesis. The σ1 receptor may sustain the long-term survival and self-renewal of stem-like cancer cells, likely due to its involvement in ER-mitochondria transactions, stress response, metabolic reprogramming, and mitochondrial dynamics. Our studies intend to extend these initial findings by investigating the consequences of the genetic knockdown and small-molecule inhibitors of the σ1 receptor in multiple cancer models. Selective targeting of the σ1 receptor may represent an effective strategy for therapeutic intervention against tumor-initiating stem-like cells in human cancers.
Nanoparticle-based delivery and combinatorial therapies for cancer
New therapeutic options are needed for locally advanced and metastatic prostate cancers that fail the current treatments, like ADT and ARPIs. The epigenetic variability among tumor cell subpopulations and consequent tumor heterogeneity promote the emergence of treatment-resistant cell clones. Our preclinical data indicate that combining epigenetic drugs (e.g., BET inhibitors) with standard chemotherapy may be an effective strategy for improving the current outcome in patients with advanced prostate cancer. Concomitant treatment with these drug combinations was highly synergistic and efficacious in preclinical in vitro/in vivo models. However, individual toxicity of the drugs and the combinations' cumulative effects may limit this approach's clinical applicability. In this project, we build biodegradable micellar nano-systems to deliver synergistic drug combinations to treat advanced prostate cancer. This nanomedicine-based approach with multi-drug loaded nanoparticles may increase the efficacy of the treatment by providing concomitant targeted delivery of rationally designed synergistic drug combinations to cancer cells while reducing the systemic exposure of normal tissues.
Targeting Lin28-dependency in liver cancer
Liver cancer is the second cause of cancer-related death, and its incidence is increasing worldwide. Hepatocellular carcinoma account for 90% of liver cancer cases. There are limited therapeutic options for the treatment of advanced hepatocellular carcinoma. The altered metabolic and immune microenvironment associated with liver cancer has a critical enabling role in disease progression and treatment failure. Lin28A/B are RNA-binding proteins that repress the biogenesis of let-7 miRNAs or enhance the translation of specific mRNAs. Many cancers exhibit upregulation of Lin28 proteins that drive malignant transformation by promoting the expression of multiple oncogenes and stem cell factors leading to the expansion of poorly differentiated stem-like tumor cells. Recent work has established that Lin28 also resides at the interface between tumorigenesis and metabolic reprogramming. In this context, our current findings suggest the possibility of modulating liver metabolism selectively by interfering with Lin28A/B proteins with a beneficial effect on metabolic liver diseases and cancer. Currently, we are examining the impact of metabolic reprogramming by targeting Lin28 in human and mouse models of hepatocellular carcinoma. In answering these questions, the project aims to provide novel and potent therapeutics for addressing advanced hepatocellular carcinoma in patients.
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