Stony Brook Cancer Center Study Shows Promise of New Approach to Treat Lung Cancer

Novel therapeutic designed to combat drug resistance; findings published in Molecular Therapy

The need for more effective lung cancer treatments is paramount given that the disease remains a leading cause of cancer deaths in the United States. New findings by a research team from the Stony Brook Cancer Center highlight a novel therapeutic that is shown to be highly effective in reducing non-small cell lung cancer (NSCLC) tumors and appears to halt drug resistance in a laboratory model. The paper is published early online in the journal Molecular Therapy.

Led by Jingfang Ju, professor in the Department of Pathology in the Renaissance School of Medicine (RSOM) at Stony Brook University and a researcher in the Stony Brook Cancer Center, the team designed a multi-targeted and multimodal tumor suppressor miRNA-129 based therapy to combat drug resistance in NSCLC by improving the stability, deliverability, and efficacy of the agent. The molecule miRNA-129 is a non-coding RNA molecule that regulates gene expression and often acts as a tumor suppressor in the human body.

The team tested this approach in a NSCLC murine model. Essentially, they combined the natural cancer-fighting molecule (miR-129) with a built-in commonly used chemotherapy drug for lung cancer (gemcitabine). Their created drug, Gem-miR-129, can enter cancer cells on its own without the need of a delivery vehicle, unlike single targeted therapy for NSCLC, and it simultaneously shuts down three different oncogenic driver proteins that help lung cancer grow and resist therapy. The driver proteins are HMGB1, YAP1, and PBX3.

"The results in the model were remarkable, with the impact of tumor shrinkage reaching more than 95 percent," said Ju, also the director of the Oncogenic Drivers and Mechanisms of Carcinogenesis research arm at the Stony Brook Cancer Center. "Additionally, the survival time for the mice treated with Gem-miR-129 increased by many weeks, which may translate to approximately 5 to 15 more years in terms of human life."

The approach and action of the new agent

Currently, in humans who have NSCLC, gemcitabine is a standard first-line chemotherapy for patients. Recent advancements in targeted therapies have improved survival for a subset of patients with NSCLC harboring significant oncogenic driver mutations, namely those with mutations in the epidermal growth factor receptor (EGFR). These patients respond to drugs called tyrosine kinase inhibitors (TKIs), which result in an EGFR blockade. Despite a good initial response to TKIs, about half of the cancers acquire resistance to TKIs.

Gem-miR-129 is designed for the subset of NSCLC tumors that develop TKI resistance. It prevents resistance because the new agent suppresses several oncogenes that are associated with both intrinsic and acquired resistance - to both chemotherapy such as gemcitabine and EGFR inhibitors.

Ju explains that once the gemcitabine-modified (Gem) drug is released from Gem-miR-129, low-dose Gem will inhibit tumor-infiltrated T regulatory cells (Ti-Tregs), which block cytotoxic T cells (CD4 and CD8) from eliminating tumor cells. By reducing Ti-Tregs, the agent can remove the inhibitory effect of the immune response on CD4 and CD8 T cells so that they can reduce the tumor burden.

"Resistance is the primary reason why current lung cancer therapies stop working for cancer patients, and for that reason, this approach is highly promising," Ju said. "In the model, we also did not see the agent causing any noticeable toxic side effects. We believe this new approach provides a proof-of-concept for future studies that could lead to clinical trials in NSCLC patients."

Ju said the next step in the team's research will be to pursue Investigational New Drug (IND) studies for Gem-miR-129. The IND process is designed to establish a drug's safety profile with the hopes of gaining regulatory approval for human clinical trials.

The research was supported, in part, by a Veterans Affairs Merit Award and by a Stony Brook Cancer Center Pilot Fund.