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  • Researchers make important new findings about how to test cancer-fighting drugs

    Researchers make important new findings about how to test cancer-fighting drugs

    INDIANAPOLIS—Researchers from Indiana University School of Medicine are discovering new ways to find out how effective a drug might be against cancer. Their findings are detailed in a new paper published by Science Advances.

    “This paper completely changes the way we need to collect tumor tissues and test for drug sensitivity,” said Harikrishna Nakshatri, PhD, a senior author of the paper. Nakshatri is the Marian J. Morrison professor of breast cancer research at IU School of Medicine and a researcher with the Vera Bradley Foundation Center for Breast Cancer Research at the Indiana University Melvin and Bren Simon Comprehensive Cancer Center. Hal Broxmeyer, PhD, a distinguished professor at IU School of Medicine who passed away in December 2021, also contributed to this study.

    Typically, tumors are collected and exposed to room oxygen, which is about 21 percent. However, different organs in the body have different oxygen levels. For example, the brain has 4.4 percent oxygen, blood 5.3 percent, and liver 5.4 percent. When cancer drugs are used on tumors in the clinical setting, they’re still in a patient’s body and are not exposed to ambient air.

    “The oxygen level in our different parts of the body is almost half of what we find in ambient air,” Nakshatri said. “Oxygen can have a different effect on the function of different proteins in the tumors. They may get activated, lose their activity level, get degraded or get stabilized. We wanted to test the tumors in a way that more closely resembles how they are in the body, so we know more about what drugs to use.”

    Researchers tested three different drugs on two different types of tumors. They split the tumors in half and tested one part in 5 percent oxygen, since that is an average oxygen level in the body, and exposed the other part to room oxygen before testing. They looked at the difference in the cancer stem cells, signaling pathways and how drugs behaved in the different oxygen levels. They found the sensitivy level of the tumor cells was different in 5 percent oxygen versus room oxygen.

    “This is a study that is now raising more questions we need to answer,” Nakshatri said. “Why do the cells react differently? Are we screening the drugs against cancer cells the right way? If we screen for drugs at the physiologic oxygen level, are we going to find different drugs that we may have missed all these years by doing the experiments at 21 percent oxygen?”

    In the future, researchers hope to study the different reactions tumors have to other various oxygen levels, like 1 percent or 20 percent. Nakshatri explained this kind of testing could act as another method of screening to determine a drug’s efficacy.

    “Suppose we identify a drug with the way we are doing right now in room oxygen, then add another layer of testing in the lab where we keep the cells at the physiologic oxygen level and compare whether the drug is working or not,” Nakshatri said. “If it works, then we can move forward to the clinical setting and it increases the chances of the drug being successful.”

    Other study authors from IU School of Medicine include Brijesh Kumar, PhD, Maegan Capitano, PhD, Yunlong Liu, PhD, Constance Temm, PhD, George Sandusky, PhD, and Amber Mosley, PhD. Read the full publication in Science Advances.

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    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.

  • IU School of Medicine research provides advances in treatment of triple negative breast cancer

    IU School of Medicine research provides advances in treatment of triple negative breast cancer

    Findings published in influential Journal of Clinical Oncology

    INDIANAPOLIS – Indiana University School of Medicine physician scientist Bryan Schneider, MD is the principal investigator of clinical trial BRE12-158, a randomized clinical study published in the prominent Journal of Clinical Oncology the primary goal of which was to compare survival in women with high-risk (those who did not fully respond to chemotherapy prior to surgery) triple negative breast cancer (TNBC) with a genomically directed therapy versus standard of care.

    The study found that in the adjuvant (following chemotherapy and surgery) setting, a single genomically directed therapy was not better than a current standard of care option, which was capecitabine. 

    “Although this study did not prove genomically directed therapy was significantly superior alone, it did provide many advances for the treatment of high-risk triple negative breast cancer. We are thankful for the 200 patients and study teams across the United States who participated in this trial,” said Schneider, a researcher at the Vera Bradley Foundation Center for Breast Cancer Research at the IU Melvin and Bren Simon Comprehensive Cancer Center; also the location where the lab research portion of this study was conducted.

    Until 2015, no therapy, in the adjuvant setting had been shown to improve outcomes for patients with TNBC. This study showed that therapy (both the targeted therapy and the standard therapy option capecitabine) was markedly better than no therapy at all.  

    “Patients with high risk TNBC who received genomically targeted therapies had superior outcomes when compared with those who received no therapy. Additionally, patients who received capecitabine – a current standard of care option for TNBC – also had superior results when compared to those who received no therapy at all,” said Schneider, who is also the Vera Bradley Chair of Oncology at IU School of Medicine.

    Twenty percent of patients who were in the study did not receive therapy of any kind, in the adjuvant setting, for the treatment of their high risk TNBC. “We found that despite a study from 2015 which showed capecitabine was superior to receiving no therapy in patients with high risk TNBC, some were still receiving no therapy,” said Schneider. “When we observe a finding like this in a clinical study, experience shows us that in the real world, the numbers are actually much higher. Hopefully, these findings will further support that all patients with high risk TNBC in this setting will be considered for additional therapy as deemed appropriate by the treating oncologist. 

    This study also found that race did not appear to impact outcomes in this high-risk population. “This finding shows that the biology of TNBC is incredibly important and clinical trials should be focused in settings where disparate outcomes are most prevalent,” said Schneider. 

    Schneider also presented these findings as part of a spotlight session at the December 7-10, 2021 San Antonio Breast Cancer Symposium, an international scientific exchange among basic scientists and clinicians, working in breast cancer. 

    Clinical study BRE-158 has yielded an important discovery and provided valuable findings for oncologists and patients with triple negative breast cancer, said Tatiana Foroud, PhD, executive associate dean for research affairs at IU School of Medicine and leader of the IU Grand Challenge Precision Health Initiative. Results from this study, which are being published in prestigious journals read around the world, are doing what we promised to do, advance treatment options for patients with this terrible disease.”
     
    An initial discovery from clinical study BRE12-158  was published in JAMA Oncology. Schneider and his colleagues found that circulating tumor DNA (ctDNA) found in a patient’s blood, in the adjuvant setting, is a marker for residual disease; meaning patients who test positive for ctDNA are much more likely to have disease recurrence than those who test negative for ctDNA.

    “Circulating tumor DNA status remains a significant predictor of long-term outcomes in these patients,” said Schneider. It should be used to stratify patients in cancer clinical trials moving forward.”   

    The findings from BRE12-158 provided the needed rationale to launch the PERSEVERE  (BRE18-334) trial, which tests genomically targeted therapies in combination with capecitabine. PERSEVERE has now opened with four patients in the study. Using ctDNA technology, PERSEVERE is enrolling and following ctDNA-positive and negative patients. “Our hope is that these patients will continue to do well, enabling us to design future clinical trials of personalized therapy or no therapy that will further improve quality of life,” added Schneider.

    Study BRE12-158 was funded by the Vera Bradley Foundation for Breast Cancer in Roanoke and the Walther Cancer Center. BRE-158 is part of the Indiana University Precision Health Initiative Grand Challenge. The study was managed by the Hoosier Cancer Research Network and enrolled at 22 clinical sites across the United States.

    Media contact: Christine Drury; Email: cldrury@iu.edu; Cellphone: 317-385-9227

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    About IU School of Medicine
    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.

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