Enhancing immunotherapies against HPV-induced cancers with Smac mimetics

Identification: Lala-Tabbert, Neena


Description

 

Enhancing immunotherapies against HPV-induced cancers with Smac mimetics
 
Neena Lala-Tabbert, Marina Fukano, Shawn Beug, Eric LaCasse, Robert Korneluk
University of Ottawa, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada
      
Human papillomaviruses (HPV) cause 5% of all cancers worldwide. In general, HPV infections are responsible for 90% of cervical cancers, 70% oropharyngeal cancers and for the majority of anal, vaginal, vulvar and penile cancers. These infections can be prevented with prophylactic vaccines, but unfortunately they are not effective against established infections. Immunotherapy has changed the landscape of cancer treatment and in recent years there have been a number of accelerated approvals for their use in a wide range of cancers. As monotherapies, these agents have demonstrated clinical activity across many tumor types; however, further improvements in the effectiveness of immunotherapies will require targeting antitumor immune response at multiple levels. One promising approach to improving these immunotherapies is with the use of small molecule inhibitor of apoptosis (IAP) antagonists called Smac mimetics (SMs). The IAP proteins represent a class of oncogenes that provide cancer cells with the ability to evade multiple death signals, including those arising from the immune system. Interestingly, cellular IAP1 (cIAP1) and cIAP2 have been identified as important cancer targets in squamous cell carcinomas due to the high rate of gene amplification for cIAP1/2 and increased transcriptional induction of cIAP2 by constitutive NF-κB activation. We have discovered that SMs can dramatically increase the efficacy of immunotherapies, such as Imiquimod and immune checkpoint inhibitors (ICIs), in several animal models of cancer. We seek to demonstrate that combination immunotherapies that include SMs will allow for better treatment efficacy and viral clearance in HPV-induced cancers. We also hope to understand the mechanisms for synergy for the combinations and to identify factors of resistance to therapy.
 
Funded by the CHEO Research Institute and the Ottawa Regional Cancer Foundation.

 

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