Trethera Secures $2.7 Million NIH Grant to Evaluate TRE-515 Combination Therapy for KRAS Inhibitor-Resistant Lung Cancer
核心洞察
Trethera Corporation (搜索) received a $2.7 million NIH SBIR grant to evaluate TRE-515 in combination with KRAS (搜索) inhibitors for treating non-small cell lung cancer.
The grant addresses a critical unmet need, as 60% of patients do not respond to KRAS (搜索) inhibitor monotherapy and those who do respond experience relapse after 8-10 months.
TRE-515 inhibits deoxycytidine kinase to block the nucleoside salvage pathway, preventing cancer cells from escaping KRAS (搜索) inhibitor treatment through metabolic adaptation.
Trethera Corporation (搜索) announced the award of a $2.7 million Small Business Innovation Research (SBIR) grant from the National Institutes of Health to evaluate the combination of its lead drug candidate TRE-515 with KRAS (搜索) inhibitor therapies for treating non-small cell lung cancer (NSCLC). The grant will fund preclinical testing in NSCLC mouse models to inform future clinical trials.
The funding addresses a significant therapeutic gap in lung cancer treatment. According to World Health Organization estimates, more than 2.5 million new cases and 1.8 million deaths from lung cancer occurred globally in 2024. Lung cancer is responsible for more deaths annually than breast, prostate, and colorectal cancer combined, with NSCLC causing 80% of lung cancer deaths.
Addressing KRAS Inhibitor Limitations
While FDA-approved KRAS (搜索) inhibitors have transformed the NSCLC market, current therapies face substantial limitations. KRAS inhibitors demonstrate only a 40% response rate, meaning 6 of 10 patients experience no clinical benefit from treatment. Furthermore, patients who do respond to KRAS inhibitor therapy find their results transient, with an average duration of 8-10 months before tumor growth resumes.
"Combining TRE-515 with targeted KRAS (搜索) therapies is intended to exploit a metabolic vulnerability in NSCLC and address the significant unmet need for the 60% of patients who do not respond to KRASi monotherapy and those who experience relapse," said Dr. Ken Schultz, Chairman and CEO of Trethera.
Novel Mechanism of Action
TRE-515 inhibits deoxycytidine kinase (dCK), the key enzyme for the nucleoside salvage pathway that becomes activated and essential for abnormal cell growth in autoimmune diseases and cancer. When treated with KRAS (搜索) inhibitors alone, cancer cells can escape destruction by using the salvage pathway to gather additional nucleosides to repair DNA damage. Combining TRE-515 with KRAS targeting drugs synergistically cripples the ability of cancer cells to grow or recover from DNA damage and enhances the therapeutic response.
"KRAS (搜索) inhibitor resistance remains a major challenge, and our data suggest that blocking the nucleoside salvage pathway directly disrupts a key metabolic escape route used by lung cancer cells," said UCLA Assistant Professor Evan Abt, grant co-investigator.
The company's approach targets a metabolic vulnerability that appears selective for cancer cells. Consistent with observations that dCK activity is relatively minimal in the regulated cell division of healthy cells, inhibiting dCK with TRE-515 has demonstrated favorable safety in addition to clinical benefit in ongoing first-in-human trials.
Strong Scientific Validation
The NIH peer review panel provided strong endorsement of the research approach. In its written summary, the panel commented that "significance and market potential are high given the need for novel drug combinations for a deadly disease with limited treatment options" and noted "potential for commercialization in a short time if the research is successful."
The review panel also highlighted that "preclinical and early phase clinical data provide additional reassurance of safety" and that "evaluation of biomarkers for the combinatorial approach so early in the drug development is a major strength." The panel noted that TRE-515 has "already shown clinical activity and demonstrates potential as a novel therapeutic agent."
Dr. Steve Dubinett, Distinguished Professor at the UCLA School of Medicine and pulmonologist, emphasized the clinical significance: "Lung cancer is the leading cause of cancer-related mortality worldwide, with limited effective therapies once the disease becomes resistant and metastatic. A novel, first-in-class drug such as TRE-515, paired with the KRAS (搜索) inhibitor class, could redefine treatment for this devastating disease."
Regulatory Momentum
The NIH grant represents the second major external validation for Trethera within six months, following FDA Fast Track designation for TRE-515 in prostate cancer. The FDA has also designated TRE-515 as an Orphan Drug for two autoimmune neurologic diseases.
"Securing this NIH lung cancer grant continues our multiple indication momentum, coming less than six months after receiving FDA Fast Track designation for prostate cancer. Such dual external validations are rare and substantiate the strength of our scientific rationale and clinical observations," said Dr. Schultz.
TRE-515 is being developed as an orally administered capsule that can be used as monotherapy or in combination to precisely target metabolic vulnerabilities in cancer and autoimmune diseases. The drug represents a first-in-class approach to inhibiting the nucleoside salvage pathway, one of two biosynthetic pathways that generate DNA precursors.