UCLA researchers from the Department of Medicine have identified an anti-cancer drug that targets mitochondrial membrane potential to selectively kill tumor cells, showing efficacy for traditionally treatment-resistant lung cancers.
BACKGROUND: Non-small cell lung cancer (NSCLC) is a devastating disease that will claim the lives of approximately 125,000 Americans in 20261. Recent advances with immune checkpoint inhibitors (ICIs) and targeted therapy have revolutionized the treatment of advanced metastatic NSCLC, but most patients eventually develop therapy resistance. In addition, tumors with mutations in the LKB1 tumor suppressor gene, which occurs in 20-30% of lung cancer patients makes tumors highly resistant to ICI’s and chemotherapy. Patients with LKB1 mutations respond poorly to standard of care treatments and have worse outcomes in multiple cancer types. Thus, it is critical to identify treatments that are not only effective for patients with LKB1 mutations, but can also pave the way for utilizing mitochondria as therapeutic targets in other cancers. The poor outcomes in this sizable NSCLC patient population underscore the need to develop effective new treatments to overcome therapy resistance. We have developed a novel small molecule drug that targets to the mitochondria and selectively kills therapy resistant lung tumor cells through inhibition of mitochondrial regulated Ca2+ flux.
INNOVATION: The research team at UCLA have identified a novel lead compound, JHSW-29 that selectively targets and disrupts mitochondrial membrane potential through disruption of the Mitochondrial Calcium Uniporter (abbreviated MCU). JHSW-29’s mechanism of action is dependent on the MCU Regulatory 1 subunit (abbreviated MCUR1), which is highly expressed in a multitude of cancers that include lung, ovarian, pancreas, breast, liver cancers. Importantly, genetic deletion and/or inhibition of MCUR1 in cardiac tissue is non-lethal. JHSW-29 disrupts Ca2+ flux in the mitochondria of tumors cells resulting in a collapse of mitochondrial membrane potential and oxidative phosphorylation. This results in cell death that is selective to cancer cells but not normal cells. The researchers have discovered that tumor cells expressing high protein levels of MCUR1 have elevated levels of mitochondrial Ca2+ flux, mitochondrial membrane potential and oxidative phosphorylation. The researchers have developed a series of companion diagnostic in parallel with development of their lead compound. This includes development of: 1) Biochemical assay for the detection of MCUR1 protein in both frozen and formal fixed tumor tissue; 2) Positron emission tomography (PET) tracer that measures mitochondrial membrane potential and oxidative phosphorylation. This PET tracer can be used to non-invasively identify therapy responsive tumors at time of diagnosis as well as longitudinally monitor therapeutic response during the course of treatment. Using this novel technology, researchers have identified patients across a broad spectrum of cancers that include NSCLC, small cell lung carcinoma (SCLC), breast, kidney and bladder cancer. Thus, this JHSW-29 represents a novel treatment option for tumors that are resistant to current therapies, and treatment response may be predicted prior to treatment using non-invasive imaging techniques.
POTENTIAL APPLICATIONS:
- Treatment of both NSCLC and SCLC lung tumor subtypes that express MCUR1 protein. This includes genetically defined lung tumors bearing mutations in LKB1, KRAS and EGFR as well as lung tumors lacking precise characterization of genetic mutations.
- Treatment of a broad spectrum of cancers that express MCUR1. These include: Ovarian, Breast, Pancreas, Kidney and Bladder cancer.
- Targeting other tumor types or tissue types with high mitochondrial membrane potential detected by non-invasive imaging techniques.
ADVANTAGES:
- Ability to use non-invasive methods (PET imaging + mitochondrial specific PET tracer) to predict treatment response.
- Selectively targets tumor cells, decreasing risk of adverse side effects.
DEVELOPMENT-TO-DATE: UCLA researchers have developed a novel anti-cancer drug, JHSW-29 that targets and disrupts mitochondrial membrane potential to induce selective cell death therapy resistant tumor cells, particularly in tumors with high expression of the MCUR1 protein. They have completed SAR and MOA studies, PK/PD and toxicity studies. They are currently testing their lead compounds in mouse models of cancer. All experiments validated in mouse models lung cancer that include: immune competent autochthonous mouse models and patient derived xenografts. They also developed a PET tracer as a companion diagnostic to predict and monitor treatment response using non-invasive imaging techniques in patients.
Keywords: Small molecule screen, mitochondrial inhibitors, lung cancer, LKB1 mutant, mitochondrial membrane potential, metabolism, PET imaging