Tango Therapeutics has achieved a significant milestone in precision oncology by dosing the first patient in its phase 1/2 clinical trial of TNG462, an MTA-cooperative PRMT5 inhibitor designed to treat solid tumors with MTAP deletions. The drug candidate, which has received Fast Track designation from the U.S. Food and Drug Administration, represents a targeted approach to addressing a genetic vulnerability found in 10-15 percent of solid tumors.
Addressing an Unmet Medical Need
MTAP deletions occur in a substantial portion of solid tumors, many of which have limited treatment options. According to Barbara Weber, M.D., President and Chief Executive Officer of Tango Therapeutics, "there currently are no FDA-approved treatments specifically for cancers with MTAP deletion." This gap in treatment options underscores the clinical significance of TNG462's development.
The phase 1/2 clinical trial will evaluate multiple aspects of TNG462's therapeutic profile, including safety, pharmacokinetics, pharmacodynamics, and efficacy in patients with MTAP-deleted solid tumors.
Mechanism of Action and Selectivity
TNG462 operates through a sophisticated mechanism that exploits the metabolic consequences of MTAP deletion. When MTAP is deleted in cancer cells, it causes accumulation of intracellular MTA, an inhibitory PRMT5 co-factor. TNG462 selectively binds to and inhibits PRMT5 in the presence of MTA, making it selectively cytotoxic for cancer cells with MTAP deletion while sparing normal cells.
This selective targeting mechanism is crucial for the drug's therapeutic potential, as it allows for cancer cell destruction without significant harm to healthy tissue. In preclinical studies, TNG462 demonstrated impressive efficacy, inducing deep tumor regressions in preclinical models of multiple cancer types.
Dual-Program Strategy
Tango Therapeutics is pursuing a comprehensive approach to MTAP-deleted cancers through two distinct PRMT5 inhibitors. Alongside TNG462, the company is advancing TNG908, a brain-penetrant MTA-cooperative PRMT5 inhibitor, in an ongoing phase 1/2 study. Weber emphasized the strategic value of this dual approach: "Each molecule has unique properties, and by advancing both programs, we have the opportunity to make a difference in a broader range of indications."
Both TNG908 and TNG462 are potent PRMT5 inhibitors that demonstrate selectivity for cancer cells with MTAP deletion, but their distinct properties may allow them to address different patient populations and tumor types.
Synthetic Lethality Approach
The development of TNG462 exemplifies Tango Therapeutics' broader strategy of leveraging synthetic lethality principles in precision oncology. The company's approach focuses on identifying and targeting critical vulnerabilities in cancer cells, particularly those arising from tumor suppressor gene loss and their contribution to cancer cells' ability to evade immune system detection.
This patient-centered approach to drug discovery represents an evolution in precision medicine, expanding beyond traditional oncology targets to address previously undruggable genetic alterations that contribute to cancer progression and treatment resistance.
