Department of Defense grants gelp CU Cancer Center researchers investigate metastasis

Two members of the University of Colorado Cancer Center have received prestigious Idea Awards from the United States Department of Defense Peer Review Cancer Research Program (PRCRP).

Founded in 2009, the PRCRP funds cancer research to support counselors, their families, and the American public. Since military personnel are exposed to dangerous environments due to the nature of their service and are at risk of developing many types of cancer, the PRCRP’s mission is to promote high-quality research for the prevention, detection, treatment and survival of cancer. .

Masanori Hayashi, MD of the CU Cancer Center, a pediatric oncologist at Children’s Hospital Colorado, received a PRCRP grant for his research on Ewing’s sarcoma, a cancer that affects children and young adults. Seventy percent of Ewing sarcoma patients respond well to a combination of chemotherapy and surgery, but 30% of patients have metastatic (disseminated) relapse in the months or years after treatment. Hayashi’s research is aimed at preventing the emergence of new metastatic lesions.

“Nobody knows why it happens, and nobody knows how to stop it,” Hayashi says of the metastasis. “All the chemo we use is 40 to 50 year old, good old-fashioned conventional chemo.”

In an effort to better target metastasis, Hayashi and his team – including Kelly Sullivan, PhD member of the CU Cancer Center – are looking at the main gene driver in Ewing, a mutation called EWS / Fli1. “About 1,500 genes are known to be regulated by this large fusion gene, and our hypothesis is that there are genes regulated by this fusion gene that direct metastasis,” he says. “Our approach uses a mouse model that I have developed to screen genes driven by EWS / Fli1, and to perform a genomic screen to identify whether genes are the drivers of metastasis.”

If those genes can be identified and inhibited, he says, metastasis could be prevented with far fewer side effects than current therapies.

“This would change the way we treat Ewing,” he says. “It would not just be chemotherapy with a blunt object, but it would be a combination. Chemotherapy is coming, but patients will also receive antimetastatic therapy. I hope this will change the outcome. What kind of goal we find, I hope that we can even do maintenance therapy for high-risk patients when they have finished chemo. “

As an assisted member of the CU Cancer Center, Hayashi works with members Paul Jedlicka, MD, Michael Verneris, MD, and Rajeev Vibhakar, MD, PhD, MPH / MSPH, to advance his career and research.

“They helped me a lot in the transition from a supervised post-doc to my own lab – coming up with new projects, learning new techniques,” says Hayashi. “For this study, much of the proposal was based on single-cell RNA sequencing and the use of CRISPR screening, which is something Rajeev has experience with. Paul is also working on a CRISPR screening project, and he has helped me a lot. Mike has considerable experience in single-cell RNA sequencing, and has been incredibly helpful. ”

The second PRCRP grant went to Cecilia Caino, PhD, a member of the CU Cancer Center, who is researching metastatic prostate cancer.

“One of the big challenges we have in the field is that for prostate cancer, most therapies target hormones – the androgen axis,” she says. But almost all patients develop resistance to those drugs and then have a more aggressive disease that moves to other parts of the body. It’s limited to the prostate, but now it can transfer to the bones or the liver or the lungs. is a really big problem, because if you start to compromise the vital organs, the patient will eventually die. ‘

Caino and her research team are investigating the role of mitochondria – the tiny energy factories in cells that help break down food into fuel – in metastatic prostate cancer. Specifically, they will study a mitochondrial protein called MIRO2, the expression of which is excessive in metastatic prostate cancer tumors. Caino has discovered that MIRO2 interacts with two other proteins, called GCN1 and GCN2, to help metastatic prostate cancer cells tolerate conditions where normal cell growth would be prevented, and wants to further explore the impact of MIRO2, GCN1 and GCN2 on aggressive metastatic prostate cancer. to investigate. . She also plans to study MIRO2 mutations that abolish tumor invasiveness and suggest a possible way to target the protein.

“We want to understand how these three proteins work together to help cells survive and move around the body,” says Caino. “When we understand that, we can come up with a strategy to keep them from moving.”

Caino says she is grateful to her supervisory committee, Scott Cramer, PhD, Heide Ford, PhD, and Joaquin Espinosa, PhD, for their help in navigating her lab setup and management of lab personnel, as well as the feedback they provided on the grant. writing and proposed funding options.

“I have also participated in internal review panels and NIH scholarship review panels that helped secure my mentoring team,” said Caino. “During the pandemic, Scott and Heide were very helpful and kept me focused on what was important. As a member of a mentor, I also gained subsidized access to shared resources from the CU Cancer Center, such as flow cytometry, functional genomics, mass spectrometry and pathology, which I developed my lab’s research. “

For her PRCRP-funded project, Caino plans to use tissue samples donated by cancer patients to compare tumors located in the prostate with tumors that have spread to the bones, liver, or lungs. She says she is grateful to the PRCRP for funding the research.

“This is one of the happiest moments so far in my twenty years as a researcher,” she says. “I recently set up my lab, and this is my first federal grant, so this means a lot to my career. It’s an honor because I feel that this panel of researchers who evaluated my proposal really liked it and the promise saw it. It encourages me that this is a great idea. ”

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