Selectively Kills EGFR+, HER2+, and HER+3 Tumors via New Mechanism, Enabling These Tumors to Overcome Resistance to Current Therapy
This first-in-class compound selectively kills cancer cells without harming normal tissues. The Epidermal Growth Factor Receptor (EGFR) family members -- EGFR, Human Epidermal Growth Factor Receptor-2 (HER2) and Human Epidermal Growth Factor Receptor-3 (HER3) -- are well established as proto-oncogenes that play key roles in the initiation and progression of a number of human cancers, including breast cancers. These proteins are important targets for therapeutic antibodies and tyrosine kinase inhibitors; however, available chemotherapy approaches, such as Cetuximab, Trastuzumab, and Lapatinib, are unable to target and inactivate all three proteins successfully and at low levels of toxicity. EGFR, HER2 and HER3 have overlapping functions such that inhibition of one or two of these proteins is insufficient. Moreover no FDA therapies are available for Triple Negative Breast Cancers (TNBC), which lack the therapeutic targets, Estrogen Receptor, Progesterone Receptor and HER2. Fifty percent of TNBCs overexpress the HER2 family member EGFR, but the HER2 mAbs and tyrosine kinase inhibitors have so far proven ineffective against EGFR+ TNBCs. Novel agents that selectively kill HER2+/EGFR+ tumors through mechanisms distinct from currently available HER2 mAbs and tyrosine kinase inhibitors could benefit a large number of breast cancer patients. Disulfide bond Disrupting Agents (DDAs) represent a new way of inactivating these oncogenes by downregulating them at the protein level.
Researchers at the University of Florida have developed a series of DDAs that may be effective for the treatment of cancers with resistance to currently available inhibitors targeting the EGFR, HER2, and HER3 enzymes. These first-in-class disulfide bond disrupting agents kill breast cancer cells and have good activity in human breast tumors propagated in animal models. In addition to breast tumors, these compounds could be valuable for treating several types of cancers that feature EGFR or HER2 overexpression such as salivary gland, head and neck, colon, lung, brain, pancreatic, and stomach cancers.
Application
Compound that kills cancer cells that overexpress the EGFR or HER2 proteins
Advantages
- Overcomes deficiency of treating breast cancer with HER2 antibody, which only specifically targets a single receptor HER2 to which 66 to 68 percent of HER2 positive tumors exhibit primary resistance
- Does not damage DNA or RNA
- Inactivates EGFR, HER2, and HER3 simultaneously, effectively overcoming resistance to currently available therapies
- Can be used in combination therapy with conventional cancer chemotherapeutics for drug resistant and metastatic HER2+ cancers
Technology
These first-in-class anticancer agents could be useful against cell proliferative disorders, specifically breast and other cancers which are modulated by HER2/HER3/EGFR genes. The compounds use optimal disulfide disrupting agents to disrupt extracellular disulfide bonds associated with the oncogenic functions of the EGFR, HER2, and HER3 proteins. Disulfide bond disrupting agents are expected to be toxic to cancer cells dependent on HER2 or EGFR for proliferation and survival but are well tolerated by normal tissues. The DDAs appear to selectively kill EGFR+, HER2+ and MYC+ breast cancer cells through induction of ER stress and potentiation of TRAIL-mediated cell death. Unlike cancer treatments using HER2-targeted antibodies (e.g., Trastuzumab and Pertuzumab), this compound simultaneously inactivates EGFR, HER2, and HER3, instead of the single receptor, HER2. This decreases a tumor's ability to develop primary resistance to the anticancer agent.
Brochure
