INDIANAPOLIS – An Indiana University Melvin and Bren Simon Comprehensive Cancer Center researcher has been awarded a five-year, $1.6 million grant from the National Cancer Institute to study ways to build bone and decrease tumor growth in multiple myeloma bone disease.
Multiple myeloma is a blood cancer that begins in plasma cells within the bone marrow. As the multiple myeloma cells build up, they form tumors and can damage and weaken bones.
G. David Roodman, MD, PhD, distinguished professor at IU School of Medicine, is leading the research to investigate a molecule developed with collaborators at the University of Pittsburgh that could repair bone, decrease tumors and improve outcomes for multiple myeloma patients on specific targeted therapies.
“We've been very interested in understanding the mechanisms underlying the horrific bone disease associated with multiple myeloma, which occurs in up to about 85 percent of patients and causes devastating pathologic fractures, bone pain and impacts survival,” Roodman said.
Previously, Roodman and colleagues had shown the importance of the marrow microenvironment on the growth of the tumor cells in the bone destructive process. They, with collaborators at the University of Pittsburgh, developed a small molecule called XRK3F2 to target that bone disease. Animal models and preclinical tissue models have shown that the molecule could have an important role also in stopping drug resistance in myeloma cells.
“This grant allows us to look at using a small molecule to show how we can overcome resistance to some of the most potent drugs that are in use for myeloma,” Roodman said. “Many patients develop drug resistance over time, and it becomes very difficult to treat them.”
Among newer treatments developed for multiple myeloma are targeted therapies called proteasome inhibitors, including the drugs Bortezomib and Carfilzomib. In models developed by Roodman’s research team, the XRK3F2 molecule enhanced the effects of these drugs in preclinical models of multiple myeloma.
The molecule also caused new bone formation in animal models, which could lead to treatments for healing bone lesions. Currently, there are no safe therapies to build bone mass that are approved for multiple myeloma bone disease.
Roodman and his team will further explore the XRK3F2 molecule to understand the mechanism responsible for its effects on multiple myeloma cells and its potential for new therapies for the disease.
IU School of Medicine is the largest medical school in the U.S. and is annually ranked among the top medical schools in the nation by U.S. News & World Report. The school offers high-quality medical education, access to leading medical research and rich campus life in nine Indiana cities, including rural and urban locations consistently recognized for livability.
Researchers at the Indiana University Melvin and Bren Simon Comprehensive Cancer Center have identified a target for colorectal cancer immunotherapy.
Immunotherapy uses the body’s immune system to target and destroy cancer cells. Considered the future of cancer treatment, immunotherapy is less toxic than chemotherapy. Colorectal cancer is the third most common cancer among men and women, yet chemotherapy remains the standard of care as limited numbers of patients respond to current immunotherapy treatment options.
The findings published May 7 in JCI Insight could provide additional treatments for a larger number of colorectal cancer patients via a new immunotherapy pathway. Researchers identified ST2 as a novel checkpoint molecule that could help T cells become more effective.
The research is a collaboration between IU School of Medicine cancer researchers Xiongbin Lu, PhD, Vera Bradley Foundation Professor of Breast Cancer Innovation and of Medical and Molecular Genetics, and Sophie Paczesny, MD, PhD, Nora Letzter Professor of Pediatrics and of Microbiology and Immunology.
Immune checkpoints are an essential part of the immune system with the role of preventing immune cells from destroying healthy cells. T cells are immune system cells that attack foreign invaders such as infections and can help fight cancer. But cancer is tricky, and often the tumor microenvironment creates ways to prevent T cells from attacking cancer cells by misusing several factors including the activation of checkpoint molecules.
Within the tumor microenvironment, the body’s immune system knows something is wrong and sends a stress signal such as the alarmin IL-33, which brings in immune cells called macrophages that express ST2 (the receptor for IL-33) to help. What is at first a “good” response is quickly overwhelmed and the macrophages become the enemy in fighting colon cancer.
The authors investigated using patient tumor genetic data and found that T-cell functionality, one of the key factors in fighting the cancer using the adaptive immune responses, is reduced in patients displaying high ST2 levels. Using tumor tissue samples from IU Simon Comprehensive Cancer Center tissue bank, researchers found abundant expression of ST2 in macrophages in tumor tissue samples from early to late-stage colorectal cancer.
“In all of the patient samples, we were able to identify ST2 expressing macrophages, which would potentially mean that targeting these ST2 macrophages would be relevant to the patients,” Kevin Van der Jeught, PhD, said. Van der Jeught is a post-doctoral researcher in Lu’s lab and first author of this study.
In preclinical mouse models, researchers found that by targeting the ST2-expressing macrophages, they were able to slow tumor growth. By depleting these inhibitory cells, the T cells became more active in fighting cancer.
Collaboration connects cancer research interests
Research collaborator and scientist at the Herman B Wells Center for Pediatric Research, Paczesny’s previous research led to the discovery of ST2 and is the subject of her National Cancer Institute “Cancer Moonshot” grant focusing on immunotherapy for pediatric acute myeloid leukemia (AML). While leukemia and colorectal cancer are very different diseases, researchers have found commonality and collaboration in the ST2 protein.
“This research is bringing together the pathway in two different diseases,” Paczesny said.
Lu’s research focuses on cancer cell biology in diseases such as triple negative breast cancer and colorectal cancer.
“We have to develop new tools and new approaches for solid tumors, and this is the kind of collaboration we need for advancing future treatments,” Lu said. Researchers from two other institutions, the University of Maryland’s Marlene and Stewart Greenebaum Comprehensive Cancer Center and the VIB-UGent Center for Inflammation Research in Belgium, have contributed to this publication.
Researchers also are exploring combination therapy with existing immunotherapy, such as PD-1 checkpoint inhibitors, which work to boost T cells directly, while attacking ST2 on macrophage cells increased T cells by stopping the inhibitors.
“Potentially through a combination of two checkpoints at work on different immune cells, we could enhance the current response rates,” Van der Jeught said.
The researchers plan to explore these findings further and pursue the development of ST2 for cancer immunotherapy.
Additional authors with Van der Jeught, Paczesny and Lu are IU School of Medicine researchers Yifan Sun; Yuanzhang Fang, PhD; Zhuolong Zhou, PhD; Hua Jiang, PhD; Tao Yu, PhD; Jinfeng Yang, PhD; Malgorzata M Kamocka, PhD; Ka Man So; Yujing Li, PhD; Haniyeh Eyvani; George E Sandusky, DVM, PhD; and Michael Frieden; Xinna Zhang, PhD, and Chi Zhang, PhD, IU Simon Comprehensive Cancer Center; Harald Braun, PhD, and Rudi Beyaert, PhD, Ghent University, Ghent, Belgium; and Xiaoming He, PhD, Greenebaum Comprehensive Cancer Center, University of Maryland.
This research was supported by IU School of Medicine Strategic Research Initiative fund; NIH R01CA203737 (Lu); and NIH U01CA232491 (Paczesny). A supplemental grant application has been submitted to NCI for funding further studies in hereditary non-polyposis colorectal cancer also called Lynch syndrome.
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