Zhejiang University: Hyperthermia as novel approach for destabilizing fusion oncoproteins

Chromosomal rearrangements widely occur in multiple human cancers, and fusion proteins produced from the rearrangements are well-defined oncogenic drivers that could be attractive targets for cancer treatment. Recently, a research team led by Prof. Hua Naranmandura and Prof. Chih-Hung Hsu from the Zhejiang University School of Medicine for the first-time revealed that Hyperthermia could destabilize fusion oncoproteins, opening a possibility for the application of Hyperthermia on the treatment of oncofusion-driven cancers. Their findings were published in a research article entitled “Hyperthermia Selectively Destabilizes Fusion Oncoproteins” in Blood Cancer Discovery, a journal of the American Association for Cancer Research.

Spontaneous remissions of various cancers have been sporadically observed in patients experiencing persistent fever, especially after febrile bacterial infections. Consequently, inactivated mixed bacterial vaccine has been experimentally used to induce fever as a means of Hyperthermia (elevated body temperatures beyond normal) in cancer patients leading to durable clinical remission, while the molecular mechanisms remain mysterious.

Several studies have reported that heat shock is able to destabilize certain proteins. “Due to lack of the evolutional selective pressure, fusion oncoprotein are probably more sensitive to Hyperthermia -induced destabilization,” said Hua Naranmandura.

As the oncogenic driver of acute promyelocytic leukemia (APL), the PML/RARα (P/R) fusion oncoprotein is the most successful clinical target in APL treatment by all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). However, relapse and drug resistance can occur due to drug-resistant mutations, and the prognosis in relapsed patients are extremely poor. After eight-year exploration, the researchers not only discovered both wild type and drug-resistant mutant P/R oncoproteins are sensitive to Hyperthermia but also identified the mechanism by which Hyperthermia specifically destabilized P/R oncoproteins. “We expect that this finding may shed light on the treatment of drug-resistant acute promyelocytic leukemia,” said Hua Naranmandura.

In the first part of this study, the authors demonstrated that Hyperthermia selectively destabilizes and degrades P/R fusion oncoprotein including its drug-resistant mutants through promoting aggregation of P/R in complex with nuclear receptor corepressors (NCoRs), recruiting E3 ligase SIAH2, and finally leading to the degradation through lysosome-dependent pathway.

Moreover, Hyperthermia and arsenic exhibited synergistic effect on destabilization of P/R in primary patient samples of 3 refractory APL cases as well as NB4 and primary APL cell transplanted zebrafish model. Surprisingly, Hyperthermia-ATO combination treatment showed apparent relief of tumor burden and significantly down-regulated P/R expression on relapsed/refractory APL patients Based on the in vitro findings and the initial clinical experience, the researchers have registered a clinical trial to evaluate the safety and effectiveness of Hyperthermia in a more systematic fashion (registration No. ChiCTR2000035656).

Pilot experiments also showed other oncofusions, such as AML1/ETO andTEL/AML1, were sensitive to Hyperthermia. Mildly elevating temperature induced aggregation and destabilization of these two oncofusions as well.

In an accompanying commentary, Hsin Chieh Wu, MD, Domitille Rérolle, MD, Hugues de Thé, MD, PhD, member of the French Academy of Sciences, of the Collège de France, wrote, “The proof of concept observations reported here could pave the way to further studies on hyperthermia-induced fusion oncoprotein degradation, particularly corepressor-associated ones or those whose size makes them prone to protein misfolding or aggregation.” They further commented, “These exciting studies again emphasize how APL has opened unexpected new biological or clinical tracks of investigations.”

“Although chemical-based approach is the mainstream, our work displays a potential non-invasive physical treatment for targeting oncoproteins,” said Hua Naranmandura. “Hyperthermia could be a powerful weapon to fight against disease. Our goal is to excavate the potential of Hyperthermia for treatment.”

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