Gene Hunt Leads to Potential Colorectal Cancer Treatment, Stanley J. Glaser Award
Summary
- Researchers at Sylvester Comprehensive Cancer Center are investigating a mutation linked to colorectal and endometrial cancer in the gene encoding XPO1.
- Preclinical studies in colorectal cancer models show the potential of combining the XPO1-targeting drug selinexor with the chemotherapy drug irinotecan.
- The study was published in Cancer Research and garnered follow-up funding from the Stanley J. Glaser Foundation.
Justin Taylor, M.D., a physician-scientist at Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine, has released a preclinical study highlighting a potential new way to treat colorectal cancer. He has secured a prestigious Stanley J. Glaser Foundation Research Award to continue the research.
The study investigated a mutation associated with colorectal cancer, in a gene encoding the cellular regulator XPO1 (exportin 1). The XPO1-targeting drug selinexor shrank tumors in preclinical models, in combination with the chemotherapy drug irinotecan, a current treatment for colorectal cancer.
“Here we have a new potential combination chemotherapy with science to back up why it might work in patients,” said Dr. Taylor, also an associate professor in the Hematology Division at the Miller School.
The study “provides a strong scientific rationale for further, collaborative preclinical work and future bench-to-bedside translation,” said Jaime Merchán, M.D., co-leader of the Translational and Clinical Oncology Research Program at Sylvester and a professor in the Division of Medical Oncology at the Miller School. “Moving these findings into the clinic seems feasible.”
Dr. Taylor and his colleagues plan to further investigate how the XPO1 mutation operates and test selinexor with other drug combinations in colorectal cancer models. These pilot studies will be propelled by the $51,500 Glaser award, which Dr. Taylor aims to parlay into a larger grant application to the National Institutes of Health.
Dr. Taylor and his team also plan to explore the implications for endometrial cancer, which can harbor the same XPO1 mutation, and claims the lives of about 13,860 women in the U.S. annually.
The new study appeared in the journal Cancer Research. Dr. Taylor is corresponding author on the study along with Hai Dang Nguyen, Ph.D., from the University of Minnesota.
From Blood Cancers to Solid Tumors
The study has its origins in earlier research on blood cancers led by Dr. Taylor while at Memorial Sloan Kettering Cancer Center.
There, Dr. Taylor and colleagues went on a quest for mutations associated with leukemia and lymphoma. They zeroed in on XPO1, a cellular protein that helps shuttle proteins and RNA from the nucleus to the cytoplasm. In 2019, they reported that XPO1 mutations resulted in the aberrant accumulation of proteins in the cytoplasm and seemed to drive certain B-cell malignancies.
At the time, they found a few instances of a separate XPO1 mutation linked to colorectal and endometrial cancers, dubbed XPO1R749Q.
When he joined Sylvester in 2020, Dr. Taylor continued to treat patients with blood cancers. In his lab, he also started delving into XPO1R749Q.
In the current study, he and his colleagues interrogated a massive dataset from 217,570 cancer patients. They found XPO1R749Q in 96 solid tumors, mainly colorectal and endometrial. The mutation is rare, but understanding it has broader implications, said Dr. Taylor.
Overcoming Resistance to Cancer Drugs
To explore how XPO1R749Q affects tumor cells, the researchers experimentally created the mutation in two colorectal tumor cell lines using CRISPR-Cas9 gene editing. They then asked what advantage the XPO1R749Q mutation conferred onto tumor cells.
XPO1R749Q didn’t make tumor cells grow any faster. Instead, the mutation made cells resistant to irinotecan and similar chemotherapy drugs, they found.
Irinotecan targets a protein involved in DNA replication, Topoisomerase I, leading to massive DNA damage and cell death. The researchers showed that XPO1R749Q counteracted this effect and kept tumor cells alive by increasing DNA repair activity.
Similarly, almost all XPO1R749Q mutations co-occurred with another mutation that results in highly damaged DNA. XPO1R749Q appears to counteract the DNAdamage, enabling tumor cell survival.
The researchers next treated their tumor cell lines with a drug that quells XPO1 activity, selinexor, and found that it could kill the cells. What’s more, combining selenixor with irinotecan shrank tumors in preclinical models of colorectal cancer.
Selinexor is currently approved for certain patients with advanced multiple myeloma. It is showing promise as a maintenance therapy in certain patients with advanced or recurrent endometrial cancer.
The combination of selinexor and irinotecan may be effective even in tumors that do not contain XPO1 mutations, said Dr. Taylor. Many tumor types contain elevated levels of XPO1, which may readily be neutralized by selinexor, he noted.
“Dr. Taylor’s research opens up a new potential strategy for overcoming resistance in advanced solid tumors, and importantly, in colorectal cancer,” the third most common tumor type in the U.S., said Dr. Merchán.
The Impact on DNA
The study not only provided a roadmap for a new therapeutic approach. It delved deeper into the actions of XPO1.
In a key finding, Dr. Taylor’s collaborators at the University of Minnesota outlined how XPO1R749Q affects DNA repair. They showed that XPO1R749Q amps up the DNA repair protein replication protein A (RPA), counteracting the effects of irinotecan. Some of the proteins shuttled to the cytoplasm by XPO1R749Q may be involved in regulating RPA.
Exploring such questions further “is key to the deep understanding of XPO1’s role in cancer and to developing novel therapeutics,” said first author Tulasigeri Totiger, Ph.D., a Sylvester postdoctoral associate. He is also planning to test the combination of selinexor with immunotherapy drugs and to investigate whether XPO1R749Q works similarly in endometrial cancer.
Dr. Taylor credits the collegial atmosphere at Sylvester with advancing the study, including interactions with researchers who have expertise in colorectal cancer. Dr. Merchán, for instance, is not a study author but provided feedback. The work was supported in part by a grant from the U.S. National Institutes of Health and funding from Sylvester.
“We are focused on translational science and on how we can get our results quickly, to help patients,” said Dr. Taylor. “It is exciting for me to apply some of the lessons we learned from studying XPO1 in leukemia to other cancers.”
The annual Stanley J. Glaser Foundation Awards reward promising faculty researchers at the University of Miami Miller School of Medicine with financial support. The benefactor, Stanley J. Glaser, was a philanthropist in South Florida and longtime supporter of the University of Miami.
Tags: cancer research, colon cancer, colorectal cancer, Dr. Jaime Merchan, Dr. Justin Taylor, endometrial cancer, Sylvester Comprehensive Cancer Center