From Fred Hutch News Service

Seeking to expand targeted therapy for lung cancer, this NIH MERIT Award will support LCFA-Grant recipient, Dr. Alice Berger’s, efforts to target lung cancer-associated gene mutation.

Targeted therapies have transformed outcomes for lung cancer patients. After reduced smoking rates, drugs that take aim at signature alterations in tumor cells are the main reason that the death rate has dropped for people diagnosed with lung cancer. Recently, Fred Hutchinson Cancer Research Center lung cancer researcher Dr. Alice Berger received a National Institutes of Health MERIT Award that will support her efforts to expand targeted therapy for lung cancer to more patients.

Inhibitors of a growth- and survival-promoting protein called epidermal growth factor, or EGFR, are one class of targeted therapy that’s helped improve outcomes patients with non-small cell lung cancer. EGFR protein is found in very high amounts in some people’s lung tumors, and the EGFR gene is often mutated such that the protein it encodes is more sensitive to EGFR inhibitors.

Dr. Alice Berger receives NIH MERIT award for work to expand targeted therapies for lung cancer

“The clinical problem that we’re addressing is that not all lung cancer patients have targeted therapy options,” said Berger, who holds the Innovators Network Endowed Chair. “But those existing therapies, such as EGFR inhibitors, only work in specific, genetically defined groups. There’s a fraction of lung cancers — 30% to 40% — that don’t have those targetable alterations.”

Berger’s MERIT Award will fund seven years of investigations into RIT1, a gene that’s mutated in a subset of non-small cell lung cancer and other tumors, including some leukemias. Her ultimate goal is to extend the power of targeted therapy to more patients with lung cancer.

Expand targeted therapies for lung cancer with RIT1 biomarker

Berger was inspired to seek out new therapeutic targets for lung cancer by the clinical advances seen for therapies that target other lung cancer-associated mutations. She linked several new genes to lung cancer — including mutated RIT1 — while participating in The Cancer Genome Atlas, a joint program between the National Cancer Institute and the National Human Genome Research Institute to molecularly characterize different cancers on a large scale.

Berger found RIT1 mutations in about 2% of non-small cell lung tumors. This may sound like a small number, but it has a big clinical impact.

“Because lung cancer is so prevalent, [that 2%] amounts to tens of thousands of people,” Berger said. Two percent of lung cancer cases translates to 13,000 people per year who likely have lung tumors driven by mutations in RIT1.

When she first linked RIT1 to cancer in 2014, very little was known about the gene or the protein it encodes. RIT1 is related to a better-studied protein called Ras, which transmits cellular signals that promote cell growth and survival. Ras is mutated in many types of cancer, including lung cancer. Berger believes that RIT1 may be turning on the same growth- and survival-promoting pathways as Ras through a different molecular strategy.

Currently there are no drugs that target the RIT1 protein, but Berger has identified several molecular pathways (for which potential inhibitors do exist) that appear to work in concert with RIT1 to promote lung tumor development, growth and survival. Her MERIT Award will allow her to further explore how these pathways intersect with altered RIT1 to cause cancer, as well as strategies to target them to potentially kill off RIT1-mutated cancer cells.

One protein, called Yap, enhances the tumor-promoting effects of RIT1.

“We think potentially that Yap activation may need to co-occur with RIT1 to drive tumorigenesis [cancer development]. That’s the hypothesis that we want to explore,” Berger said.

She and her team have also pinpointed a separate molecule that may control the amount of RIT1 in cancer cells, and another that links RIT1 to cell division — each opening a different potential avenue for hamstringing RIT1-dependent tumors.

Fred Hutch’s ties to Seattle Cancer Care Alliance and its deep scientific resources have been central to the success of her group’s work, Berger said. This includes studying the only preclinical animal model of RIT1-driven tumors with the help of the Hutch Preclinical Modeling shared resource. These special mice will allow Berger and her team to study how RIT1 promotes tumor development and intersects with other molecular pathways, as well as test potential drugs to target these tumors.

“We also interact a lot with [Hutch and SCCA lung cancer specialist] Christina Baik and the lung cancer medical oncologists, which helps us to remain focused on our ultimate goal of improving survival and outcomes for patients with lung cancer,” she said.