Translation of mRNA into protein represents a rate limiting step and is potential therapeutic vulnerability in cancer. The translation of cancer drivers, such as oncogenes and growth factors, is frequently regulated at the level of translation initiation and requires the activity of an RNA helicase eIF4A that facilitates the unwinding of regions of secondary structure at the 5' untranslated region of mRNAs. Many of these mRNAs have longer polypurine-rich 5' UTRs and an increased frequency of upstream open reading frames.

The development of specific eIF4A helicase inhibitor, Zotatifin, by eFFECTOR Therapeutics currently undergoing a Phase I clinical trial, therefore, represents an exciting ne...

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Translation of mRNA into protein represents a rate limiting step and is potential therapeutic vulnerability in cancer. The translation of cancer drivers, such as oncogenes and growth factors, is frequently regulated at the level of translation initiation and requires the activity of an RNA helicase eIF4A that facilitates the unwinding of regions of secondary structure at the 5' untranslated region of mRNAs. Many of these mRNAs have longer polypurine-rich 5' UTRs and an increased frequency of upstream open reading frames.

The development of specific eIF4A helicase inhibitor, Zotatifin, by eFFECTOR Therapeutics currently undergoing a Phase I clinical trial, therefore, represents an exciting new opportunity for the treatment of cancers that lack targeted therapies like triple negative breast cancer (TNBC). TNBC is a biologically heterogeneous and clinically important subtype because if it were considered a distinct disease, TNBC would rank as the 5th leading cause of cancer deaths in women. TNBC also is more prevalent in younger premenopausal women especially African Americans. Importantly, effective treatment of TNBC with Zotatifin as a therapeutic agent ultimately will require combination with standard-of-care chemo- and immunotherapies, since single agents inevitably fail leading to relapse.

We have developed and extensively characterized a series of p53-null preclinical mouse models of TNBC. These mouse models have an intact immune system that will allow us to determine the effect of single agent and combination therapies on both the tumors and immune microenvironment. These preclinical models will also facilitate studies of treatment of metastatic disease, which is the cause of mortality in the majority of cancer patients. Our proposed studies will optimize and elucidate mechanisms of combination chemo- and immunotherapy with Zotatifin across TNBC models to help inform the design of future clinical trials.

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