DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Posted February 5, 2021

Rosa Lapalombella, Ph.D., The Ohio State University

Rosa Lapalombella, Ph.D., The Ohio State University Dr. Rosa Lapalombella

The Food and Drug Administration (FDA) recently approved XPOVIO ® (selinexor), for relapsed/refractory multiple myeloma and diffuse large B-cell lymphoma. The Congressionally Directed Medical Research Programs’ Peer Reviewed Cancer Research Program (PRCRP) funded the preclinical research for this breakthrough in blood cancer treatment.

In Fiscal Year 2013, PRCRP funded The Ohio State University’s Dr. Rosa Lapalombella’s research aimed at identifying novel therapeutic targets for blood cancer treatment, using Chronic Lymphocytic Leukemia (CLL) as the model system. She found that the overexpression of a protein called exportin (XPO1) led to functional disruption of tumor suppressors. Her work advanced both the development of selinexor in the initial Phase 1 study and led to combination studies of XPOVIO ® (selinexor) with ibrutinib. Ultimately, work initiated by Dr. Lapalombella contributed to clinical trials and FDA approvals. The drug is marketed in tabular form, making it easy for doctors to administer and convenient for patients to take.

“It is patient-friendly relative to being a pill and not as toxic as chemotherapy when supportive care is given. It is a precision drug that influences one target, but it can affect many pathways at the same time,” said Dr. Lapalombella. She added that the researchers determined dosing by carefully addressing and correcting for the side effect of reduced appetite using laboratory mice models.

This is positive news for Veterans who are being treated for blood cancers linked to Agent Orange exposure during service in Vietnam. “There is some evidence that exposure to these defoliants led to development of a more aggressive form of CLL, and that exposure of fathers also led to an increased incidence of leukemia in their children,” Dr. Lapalombella said. The new drug may also present better treatment options for active duty Service members who are exposed to other chemical agents in the field.

How It Works

Dr. Lapalombella’s initial work funded by PRCRP demonstrated that inhibiting XPO1 nuclear export selectively killed CLL cells in culture. With five separate follow on grants, her team built upon her early work, studying wild-type XPO1 and a mutated form of XPO1. The research suggested that a certain level of wild-type XPO1 is essential to cellular health. However, mutant XPO1 cell lines displayed a growth rate that was higher than the wild-type parental cell lines. The research laid the groundwork for the clinical work to begin testing a new class of drugs to treat blood cancers.

In addition to the military, the newly approved drug has applications for the civilian population. Dr. Donna Kimbark, Program Manager of PRCRP said the convenience factor of taking a pill in an outpatient setting instead of going to a medical facility for an infusion enhances quality of life for cancer patients. “It’s the holy grail of pharmaceuticals to have an oral form of a drug,” she said.

While XPOVIO ® is highly effective in treating blood cancer, it suppresses tumors and Dr. Lapalombella believes the new drug, in combination with others, has the potential to be effective in the treatment of multiple other cancer types.

Dr. Lapalombella credits the PRCRP Career Development Award she received 7 years ago as the catalyst that set in motion the research by her group and others that culminated in the development of XPOVIO ®. “It really did a lot for me. It was the opportunity that jump-started my career,” she said.

Rosa Lapalombella, Ph.D., The Ohio State University Dr. Rosa Lapalombella and her research team at the Ohio State University

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Last updated Friday, February 5, 2021