Chemotherapy remains a cornerstone of treatment for head and neck cancers, the seventh-most common cancer type worldwide. However, the disease is often diagnosed at a late stage once it has already spread to other organs, and the majority of patients on active treatment will develop resistance to chemotherapy within a matter of months, showing a prominent avenue for designing more effective care strategies.
New collaborative research from multiple departments at VCU—including VCU Massey Full Cancer Center, VCU Institute of Molecular Medicine (VIMM), VCU Center for Drug Discovery, the VCU Department of Medicinal Chemistry, and the VCU Department of Cellular, Molecular and Genetic Medicine—points to a specific multifunctional protein, MDA-9, as a significant driver of head and neck tumors and a mediator of drug resistance.
A New Target for Head and Neck Cancer
The study found that a small molecule drug, IVMT-Rx-4, selectively blocks the function of the MDA-9/Syntenin protein, limiting, in some cases completely preventing, the spread of head and neck squamous cell carcinoma (HNSCC) in preclinical cancer models, with no observed toxicity. A percentage of the models were tumor-free after treatment. This inhibition is achieved, in part, by interfering with the interaction between MDA-9/Syntenin and its partner proteins that are essential for its oncogenic functions.
“Our study provides new insights into the genetic regulation of HNSCC, identifies a novel direct drug target and establishes an innovative drug as a promising chemical probe that may inform the development of more effective cancer therapeutics,” said study senior author Paul B. Fisher, MPh, Ph.D., FNAI, the Thelma Newmeyer Corman Endowed Chair in Cancer Research at VCU Massey and the founding and current director of the VIMM.
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Targeting the Root of Resistance
MDA-9/Syntenin plays an essential role in maintaining cancer stem cells’ function in HNSCC. These cells are the root cells driving tumor growth and may mediate resistance to therapies like radiation, chemotherapy, and immunotherapy. The analogy of weeds is apt: just as removing only the leaves above ground allows weeds to regrow, eliminating cancer cells without targeting stem cells leaves the potential for recurrence. The team demonstrated that IVMT-Rx-4 can effectively target and eradicate these cancer stem cells in HNSCC, preventing the formation of new tumor cells and overcoming chemotherapy resistance.
The drug also suppresses BMI1, a functional marker of cancer stem cells in HNSCC, and can reverse the properties of cells that have become resistant to chemotherapy. This is particularly important for addressing cisplatin resistance, a major challenge in HNSCC treatment. By blocking increases in cisplatin-resistant stem cells, IVMT-Rx-4 offers a promising avenue for treating advanced, therapy-resistant cancers.
A Potential Breakthrough
The collaborative team, including QingGuo Xu, Ph.D., of the VCU School of Pharmacy, is exploring avenues for IVMT-Rx-4 to be taken as an oral medication. “The ultimate hope is that this approach will increase survival, and, with advanced refinement, could actually lead to a method where the cancer will not recur,” Li said. “This long-term goal would be a real beneficial outcome for HNSCC patients.”
