TMIC-02. Selective inhibition of lactate dehydrogenase to alter the tumor microenvironment and improve therapeutic response in glioblastoma

Glioblastoma (GBM) remains one of the most challenging cancers to treat, with abysmal overall survival rates and no major advances in disease-modifying chemo- or immunotherapeutic agents in more than 20 years. Resistance to existing therapies such as radiation therapy (RT) and temozolomide (TMZ) is also problematic. Challenges associated with developing new treatments include a GBM cellular metabolic profile that promotes proliferation and conveys resistance to current modalities, the controversial existence of glioblastoma stem cells (GSCs) which may contribute to treatment resistance and disease recurrence, and unique populations of immune cells and their exclusion from these tumors. Aerobic glycolysis, well established in GBM, plays an important role in resistance to both RT and TMZ, thought to be due to the low oxidative activity. The tumor microenvironment (TME) is also shaped by aerobic glycolysis and contributes to immunosuppression by disrupting the function of immune cells, making GBM immunologically “cold.” As a result, immunotherapy has not demonstrated therapeutic benefit in GBM and many strategies seek to improve immuno-infiltration. Here we present NCI-006, a novel and selective LDH inhibitor with in vivo activity and good pharmacokinetics, as a potential treatment for GBM. NCI-006 has direct inhibitory activity on cell viability and potently decreases lactate and acid secretion while simultaneously increasing oxygen consumption. In vivo administration of the drug in a syngeneic mouse model via direct infusion from implantable osmotic pumps demonstrates significant changes in the tumor microenvironment, including decrease in LDHA, PD-L1, CD133, and CD163 expression. Combination studies with radiation and temozolomide are ongoing.