The literature has underlined an association between HER2 activating mutations in colorectal cancer and resistance to therapy. While these mutations reduce the efficacy of EGFR antibody agents such as cetuximab the tumors remain responsive to dual HER2 targeted therapy with tyrosine kinase inhibitors like neratinib(1). Additionally, while we detect activating mutations in about 7% of colorectal cancer subjects other researchers most notably Kloth et. al have determined the prevalence of HER2 mutation in patients with Lynch Syndrome to be as high as 15%. This finding suggests that much like with breast cancer and non-small cell lung cancer, the ErbB family of receptors (EGFR (ErbB-1), HER2/c-neu, HER3, and HER4 may play a significant role in colorectal cancer, thus perhaps providing novel new therapeutic targets especially for those with Lynch syndrome.
Lynch syndrome or hereditary nonpolyposis colorectal cancer is an autosomal dominant genetic condition that accounts for 3-5% of colorectal cancers. Individuals with Lynch syndrome have an 80% lifetime risk of colon cancer with a mean age of presentation at age 44 years. Treatment of those with the condition often requires far more extensive resection of the colon. Although tumor vulnerability in Lynch Syndrome primarily arises from defective DNA mismatch repair, this finding of increased HER2 mutation makes me consider exploring whether the vulnerability to develop colon cancer in this condition can be modified by modulating the EGFR pathway.
The development of Cimavax, a cancer vaccine developed at the Cuban Center of Molecular Immunology targeting EGFR provides a tool whose utility is worth exploring. By raising antibodies against EGF this vaccine has the potential to favorably influence tumors that may be largely driven from EGFR over-activation. While the agent is currently only being tested to treat non-small cell lung cancer the role of EGF antibody treatment in colorectal cancer is well established. As a preliminary feasibility study, we will conduct a study utilizing a mouse model for Lynch Syndrome.
There are a number of mouse models for Lynch Syndrome. We will utilize MSH2 KO mice. Msh2 homozygous mutant mice that survive more than 6 months of age develop GI and skin tumors. In this study I propose to take 2 sets of these mice. The control mice will be left untreated. Those surviving more than 6 months will be sacrificed. The tumor size and metastasis will be estimated. The test arm mice will be injected with a CIMAVAX like the agent at baseline. Animals in the test group will similarly be sacrificed after 6 months and the results compared to control. If there is in a therapeutic effect this will likely be manifested as [1] delay in tumor development or [2] reduction in the size of tumor [3] decrease in metastatic foci. If this strategy proves efficacious one may consider utilizing a similar prophylactic strategy. The feasibility of this intervention will certainly also be determined by the inherent toxicity of the therapeutic agent itself.
Achieving a novel non-surgical prophylactic strategy in patients genetically predisposed to cancer by silencing, repairing, replacing vulnerable genes, or inhibiting their expression represents a new frontier in cancer therapeutics.
