Brain and other nervous system cancer is the ninth leading cause of cancer death in the United States. Compared to other cancers, brain and other nervous system cancer are relatively rare. However, it is a significant complication and highly unmet medical need.
In 2020, there were 23,890 new cases of brain and other nervous system cancer and 18,020 deaths from this disease in the US. This cancer is slightly more common in men than women and among those with certain genetic syndromes. The rate of new cases of brain and other nervous system cancer was 6.4 per 100,000 men and women per year based on 2013–2017 cases, age-adjusted.
MD2 Biosciences, Inc. has identified a first-in-class-β-catenin inhibitor as a novel approach to treat brain cancer. WNT signaling starts at the cell surface and extends into the nucleus through its key player, β-catenin. Wnt signaling controls the expression of numerous genes that regulate cell proliferation, differentiation, and survival. The concentration of β-catenin is tightly regulated by the degradation machinery made up of GSK3β, CK1, APC, and AXIN. Direct targeting of β-catenin is considered the safest and most efficient therapeutic approach against the WNT pathway. Our ‘β-catenin inhibitors’ directly target β-catenin protein in the cytoplasm and reduce burden in the nucleus. Since β-catenin is known to induce transcriptional expression of PD-L1 to promote glioma immune invasion targeting β-catenin considered a highly targeted therapy.
Combination treatment option where the standard of care agents alone show limited benefit
Combination treatment option with KRAS inhibitors in the clinic, FDA approved BRAF / MEK inhibitors/immunotherapy.
Globally, colorectal cancer (CRC) is the third most common type of cancer, making up about 10% of all cases. In 2017, there were 1.8 million new cases and 896,000 deaths from the disease. The global CRC therapeutics market (in the eight major markets) is expected to grow from USD 9.1 billion in 2019 to USD 11.5 billion by the end of 2025 at a Compound Annual Growth Rate (CAGR) of 3.94%. Therefore, therapeutics that can cure CRC will have a significant societal impact and large market opportunity.
Approximately 90% of sporadic CRCs contain mutations in components of the Wnt/β-catenin signaling pathway. These mutations are found in the earliest neoplasms suggesting that this pathway serves as a critical gatekeeper to prevent colorectal carcinogenesis. Most tumors contain a mutation in a single component of the pathway, although recent data from the cancer genome atlas consortium indicates that mutations in multiple components can co-occur. The majority of mutations, some 85%, map to 'hotspots' within APC and often lead to the expression of a truncated APC protein from this allele. This truncated protein is incapable of incorporating into a function β-catenin destruction complex. Thus, when the wild-type APC is inactivated by mutations or lost through loss of heterozygosity, β-catenin levels inappropriately accumulate in the cell, leading to an aberrant expression of Wnt/β-catenin targeting genes and the development of benign adenomas. As these adenomas accumulate additional mutations in other signaling pathways, they transition into carcinomas. Therefore, CRC is a disease of Wnt/β-catenin signaling, where β-catenin/TCF complexes bound to Wnt-responsive DNA elements driving pathogenic expression targeting genes. The available standard of care agents’ therapy is limited to WT cancer cells and not to the mutant cancer cells. Additionally, the standard of care agents is known to cause irreversible side effects to patients such as chemotherapy-induced peripheral neuropathy, etc. with limited therapeutic benefit.
At MD2, we are specifically targeting beta-catenin directly to treat both WT and mutant cancer cells with our small molecule drugs. Our direct β-catenin inhibitors target β-catenin in the cytoplasm and thus reduce burden in the nucleus. In contrast, our methodology relies on small molecule drugs to be direct inhibitors of β-catenin to reduce the burden to the nucleus and represents a first-in-class approach for treating CRC.