Small Molecule Inhibitor Boosting The Efficacy Of Therapeutic Ionizing Radiation

SUMMARY

• Radiotherapy and immunotherapy are used to treat many cancer types, yet only 50% and 20% of patients respond, respectively. Resistance to therapy presents a large problem.

• N6-methyladenosine (m6A) modification is commonly found in on RNA in eukaryotic cells. By binding to m6A sites, YTHDF2 (YTH N6-Methyladenosine RNA Binding Protein 2) modulates the translation efficiency of RNA transcripts, thereby leading to RNA degradation.

• YTHDF2 expression is induced by radiation and immunotherapy, and negatively correlates with patient survival (analysis from cancer database). The faculty inventor demonstrated a novel approach where inhibition or deletion of YTHDF2, either by inhibition or genetic manipulation of host cells, enhances efficacy of radiation or immunotherapy. Therefore, manipulation of YTHDF2 in immuno- and radiotherapy may lead to overcoming therapy resistance.

• Additionally, there are several current clinical trials to alleviate immunosuppression during chemo-radio or immunotherapies. Trials focusing on depleting or altering myeloid derived suppressive cells (MDSCs) have so far been ineffective. Ipilimumab depletion of regulatory T cells has shown a 20% long-term survival benefit.  The innovated strategy of modulating YTHDF2 in cancer therapy will alleviate suppression from both MDSCs and Tregs, synergizing with radio- and immunotherapy, opening a new avenue in clinical cancer treatment.  

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ADVANTAGES

ADVANTAGES

• Addressed poor patient response to radio- and immunotherapy by overcoming barriers of suppressive cells to improve the adaptive immune response.

• Reduces radiation-induced metastases.

• Better therapies to alleviate immunosuppression.

APPLICATIONS

• Radiotherapy
• Immunotherapy
• Enhances the antitumor immunity and therapeutic efficacy of  radiation and immune checkpoint inhibitors

PUBLICATIONS

• Manuscript in review

• In vivo mouse models