Teon Therapeutics
Antagonizing Metabolic Pathways in the Tumor Microenvironment

Cancer is the second most common cause of death in the world, accounting for an estimated 10 million incidences and 6 million cancer deaths annually. Traditional treatment therapies though effective, tragically come with their own set of limitations and long-term side effects.

“While chemo and radiation therapy, the mostly widely used primary treatment, kills both cancer and normal cells, target therapy is solely focused on killing cancer cells without inducing immune countermeasures. Anti-PD-1 drugs in immunotherapy on the flipside face resistance from many tumors due to insufficient rectification of the immunosuppressive tumor microenvironment (TME) and the limited reinvigoration of anti-tumor immunity,” explains Lina Yao, Founder and CSO, Teon Therapeutics.

The acute need for a comprehensive treatment therapy without the baggage of side effects has led researchers to turn their focus on G protein-coupled receptors (GPCRs), the most commonly exploited targets in modern medicine. These cell surface receptors regulate a wide variety of human physiological processes, including growth, metabolism, and homeostasis. GPCRs are desirable targets for cancer drugs as they also regulate a broad range of signal transduction pathways that are relevant in cancer cells: EGFR/ Ras (proliferation), ATF4/CHOP (cell stress), chemokine (metastasis), and p53 (apoptosis) signaling. In addition, GPCRs are very selective and druggable, proving why 30 percent of the drugs in the market are GPCR small molecules. This is the R&D direction California-based Teon Therapeutics is founded on, developing a portfolio of single-target small molecules that antagonize metabolic signaling pathways in the tumor microenvironment.

The clinical-stage bio-pharmaceutical start-up takes a unique approach to improve the tumor site and reinvigorate anticancer immunity by targeting key GPCRs and enzymes in the TME that are upregulated on immune cells and cancer cells. “Our GPCR small molecule inhibitors target both immune cells and cancer cells that are highly active in the TME, restoring anti-tumor immunity and suppressing cancer cell proliferation. This gives the benefits of both anti-PD-1 and target therapy,” says Dr. Yao.

The metabolic activity of cancer cells plays a critical role in the immunosuppressive state of the TME. Solid tumors are very hypoxic, upregulating A2B receptors on cancer and immune cells. Hypoxia also upregulates CD39/CD73 to generate large amounts of adenosine (up to 100 μM), which activates adenosine receptors (A2A and A2B) on immune and cancer cells, consequently inhibiting immune function and promoting cancer cell survival. “As A2B is a low-affinity receptor that requires high adenosine concentration to activate, its expression and activation occur only under pathological conditions, such as cancer. That is why we target a highly dynamic GPCR like the adenosine A2B receptor,” explains Dr. Yao.

Teon’s lead program TT-702 is an adenosine receptor antagonist and specifically targets the A2B receptor, which is over-expressed on various types of tumor cells, immune cells, and tumor-associated fibroblasts. High levels of adenosine in the TME activate the A2B receptor, triggering tumor cells to grow and suppress T-cells, allowing the cancer cells to avoid immune detection. TT-702 prevents the A2B receptor from being activated by high levels of adenosine, which prevents cancer cell growth, invasion, and metastasis and enhances the anti-tumor immune response.

The bio-pharmaceutical start-up’s experienced team is rapidly developing and expanding the GPCR-focused pipeline of novel therapies to benefit as many cancer patients as early as possible. “Our A2BR-specific antagonist has entered Phase1 trials and is projected to finish up by the end of the year. The TT-816, a novel GPCR antagonist, is also geared up for Phase1 by May this year,” says Dr. Yao on the company’s roadmap.