May 07, 2021

In laboratory investigations, Mayo Clinic researchers found that cancers with inherent or pharmacologically-induced defects in the ataxia-telangiectasia mutated breast cancer gene 1-breast cancer gene 2 (ATM-BRCA1-BRCA2) DNA repair pathway are hypersensitive to a novel form of proton beam therapy. The investigators call the new treatment biologically enhanced particle therapy (LEAP) and believe the advanced delivery technique is poised to change the paradigm of radiation oncology treatment. Mayo Clinic researchers shared results of the study in the March issue of Cancer Research.

"Disruption of the ATM-BRCA1-BRCA2 DNA repair pathway by genetic and epigenetic mechanisms is commonly observed in cancer," says Robert W. Mutter, M.D., a radiation oncologist and physician-scientist at Mayo Clinic's campus in Rochester, Minnesota, and study investigator. "Identifying treatments that specifically target DNA repair-deficient tumors while sparing repair-proficient normal tissues has been a priority. For example, mutations in BRCA1 and BRCA2, key double-strand break repair genes, are the most common cause of hereditary breast and ovarian cancers. Germline and somatic alterations in these genes are also commonly observed in multiple other cancer types."

Dr. Mutter and his colleagues found an up to threefold improvement in LEAP efficacy in ATM-BRCA1-BRCA2-deficient tumors compared with the same dose of conventional photons or protons. In addition, the researchers found that administering an ATM inhibitor in combination with LEAP could hypersensitize repair-proficient tumors by rewiring tumor cell DNA repair mechanisms. Dr. Mutter says a surprising finding was that ATM inhibition could uniquely enhance the effectiveness of LEAP, but not inhibitors of other DNA double-strand break repair inhibitors such as Rad3-related protein or DNA-dependent protein kinase.

Dr. Mutter believes the findings could lead to a fundamental change for radiation therapy. "To date, the primary rationale for administration of protons in the clinic has been their distinct physical characteristics, which enable better normal tissue sparing compared with traditional photon-based radiotherapy," says Dr. Mutter. "LEAP enables the personalization of radiotherapy based on the relationship between the patient's tumor biology and the unique biologic responses induced by LEAP."

Translation of LEAP to the clinic

Zhenkun Lou, Ph.D., an oncology researcher and renowned expert in the DNA damage response pathway, is the co-principal investigator of the study. He and Dr. Mutter, along with physicists and radiation biologists at Mayo Clinic's campus in Rochester, Minnesota, have been collaborating on the LEAP project for several years. For example, LEAP requires new planning techniques optimized by physicists in Radiation Oncology whereby energy deposition from particles is concentrated at the molecular level, which creates more complex and difficult to repair DNA damage within cancer cells.

Dr. Mutter and fellow investigators are preparing clinical trials to examine LEAP's safety and efficacy. They note potential application to several tumor types, including tumors that are resistant to conventional radiotherapy. "We are thrilled about this new opportunity to bring precision medicine into the field of particle therapy for our patients," says Dr. Mutter.

The Mayo team is also studying carbon ion therapy. Carbon has an even higher energy deposition pattern than the current proton LEAP protocol, and the investigators believe tumors with defects in the ATM-BRCA1-BRCA2 pathway also may be highly sensitive to that modality. The carbon ion therapy project at Mayo Clinic in Florida is scheduled for completion by 2025.

"Emerging evidence also suggests that proton LEAP and carbon ion therapy may induce a more vigorous anti-tumor immune response, which could also open new avenues for combinations with immunotherapy to help prevent cancers from evading the immune system," says Dr. Lou.

"Mayo Clinic continues to invest heavily in particle therapy given the potential to improve patient outcomes from a number of standpoints," says Dr. Mutter. "Instead of a one-size-fits-all approach, we can begin looking at the tumor's molecular features and select the best radiation therapy modality. The tumors themselves can identify patients best suited for proton therapy and, in the future, carbon ion therapy, as well as their combination with pharmacological agents."

For more information

Zhou Q, et al. Inhibition of ATM introduces hypersensitivity to proton irradiation by upregulating toxic end joining. Cancer Research. In press.