Researchers at UT Health San Antonio have identified a potent new class of anti-cancer drugs that target oral cancer cells while leaving other cells unharmed. The new drug class also has shown promise in stopping other types of cancer. The researchers tested the drugs, broadly referred to as capsazepine analogs, against oral and other types of cancers in preclinical and animal studies.
“Our main goal was to develop cancer-targeting drugs to effectively treat advanced and recurrent oral cancer. This is important because oral cancer is a deadly disease with a five-year survival rate of only 40%,” said Cara Gonzales, DDS, PhD, an associate professor in the UT Health San Antonio School of Dentistry’s Department of Comprehensive Dentistry.
“Oral cancer is rarely diagnosed in its earliest stages when it can be cured. About 75% of patients come to the clinic with advanced disease, dramatically lowering their chance of survival,” Gonzales said.
The team’s previous research showed that capsazepine is a potent cancer killer. Capsazepine is a synthetic cousin of capsaicin, the substance in chili peppers that gives them their heat. While studying oral cancer pain, the team discovered that capsazepine has significant cancer-fighting activity through a cancer-selective mechanism of action.
In collaboration with the Center for Innovative Drug Discovery, a partnership of UT Health San Antonio and the University of Texas at San Antonio (UTSA), more potent capsazepine analogs were developed with significantly stronger anti-cancer efficacy in mouse models of oral cancer and no adverse effects on healthy tissue.
The researchers synthesized 30 new compounds whose chemical structures were based on capsazepine and screened them based on their ability to kill oral cancer cells in culture. Lead compounds CIDD24, CIDD99, and CIDD111 were validated in mouse models of human cancer.
Next, the researchers focused on the most effective lead compound, CIDD99, which eradicated the tumors while leaving normal healthy tissue unaffected. Plus, CIDD99 sensitized oral cancer cells to traditional chemotherapies, so much lower doses of chemotherapy could be used with dramatically greater effectiveness and fewer side effects.
CIDD99 also was effective against a panel of other cancer types and, therefore, may provide a new therapy for multiple cancers with fewer side effects than traditional chemotherapies.
“As we got further into our research, we found that CIDD99 also is effective against non-small-cell lung cancer, triple-negative breast cancer, and prostate cancer cells,” said Gonzales.
“These results are very exciting because no new drugs have been developed in over 40 years to treat oral cancer. While immunotherapy works very well, it is only effective in a small group of patients. Our compounds may provide a new class of drugs that may be effective for all oral cancer patients,” Gonzales said.
UT Health San Antonio and UTSA have a patent on the three drugs through the Office of Technology Commercialization, which serves both universities as a catalyst for stimulating innovation and entrepreneurship among faculty, staff and students, and industry partners through the UT System.
The team is now working with venture capital companies to apply for Small Business Technology Transfer grants and an American Cancer Society Mission Boost Phase 1 grant to conduct additional preclinical studies that are required before applying to the US Food and Drug Administration (FDA) for an Investigational New Drug (IND) status. An IND designation authorizes the administration of an experimental agent in humans, enabling future clinical trials.
“These grants will help us generate additional data regarding safety, toxicity, and how they work in the body that will get us ready to submit our FDA application for human trials,” said Gonzalez.
The first study, “Synthesis and SAR of Novel Capsazepine Analogs With Significant Anti-Cancer Effects in Multiple Cancer Types,” was published by Bioorganic & Medicinal Chemistry. The second study, “The Novel Capsazepine Analog, CIDD-99, Significantly Inhibits Oral Squamous Cell Carcinoma In Vivo Through a TRPV1-Independent Induction of ER Stress, Mitochondrial Dysfunction, and Apoptosis,” was published by the Journal of Oral Pathology & Medicine.