Genomic study points to new treatment approaches for advanced small-cell lung cancer
A study of advanced small-cell lung cancer (SCLC) led by researchers at the OSUCCC – James has identified molecular patterns linked to patients developing resistance to certain therapies. Published in the journal JTO Clinical and Research Reports, the study examined more than 60 tumors from five patients. The researchers identified distinct mutational and molecular changes in four SCLC subtypes. The findings provided insights into the patterns’ treatment resistance and could offer new targets for the development of more effective immunotherapy and other therapies for advanced SCLC, which progresses quickly and is usually fatal. SCLC accounts for up to 15% of lung cancer cases worldwide. The disease often responds well to chemotherapy when first diagnosed but then recurs in a lethal, treatment-resistant form. “Advanced SCLC often does not respond as well to immune therapies that are effective in other types of lung cancer, and the reasons for this are poorly understood,” says principal investigator Sameek Roychowdhury, MD, PhD, a medical oncologist and member of the OSUCCC – James Translational Therapeutics Program. He is also an associate professor in the Ohio State College of Medicine’s Division of Medical Oncology, and medical director of the OSUCCC – James CLIA Cancer Genomics Laboratory.
“Our findings suggest that the causes of treatment resistances in advanced SCLC may be subtypespecific,” says Roychowdhury. “They also highlight the importance of tumor genomic studies to identify the most effective therapies for these patients and to support development of new therapies for this oftenfatal disease.” Genomics is the process of identifying cancer-related mutations that drive the growth and spread of cancers. Oncologists can gather specific genomic information from individual patients to help match patients with the best therapy based on their unique tumor characteristics. This concept is referred to as precision cancer medicine, an approach that has important significance in metastatic and rare forms of cancer for which treatment options are often limited. “Understanding the specific drivers of a person’s cancer can help us identify potential alternative treatment options through clinical trials that would not have been possible otherwise,” Roychowdhury adds. For this study, Roychowdhury and his colleagues analyzed genomic DNA and total mRNA from tumor cells removed from five deceased patients with advanced SCLC, along with circulating tumor DNA. The tissue was obtained as part of a rapid research autopsy study that originally was supported by a Pelotonia Idea Grant. Tissue was collected within 16 hours of each patient’s passing, minimizing the molecular changes that occur in cells after death. The five patients had consented to undergo a research autopsy soon after death to allow the researchers to collect and evaluate many tumors. The researchers used sequencing technologies to identify genetic and molecular changes in four SCLC tumor subtypes. Many of the changes are associated with resistance to immune therapy and other treatments. “Our results need to be validated by larger studies,” says Roychowdhury, “but they suggest that subtyping SCLC patients before systemic therapy could someday play a role in drug development and therapy selection.”
Finding a way to stop chemotherapy from damaging the heart
There could be an intervention on the horizon to help prevent heart damage caused by the common chemotherapy drug doxorubicin, new research suggests. Scientists at the OSUCCC – James found that this chemo drug, used to treat many types of solid tumors and blood cancers, is able to enter heart cells by latching onto a protein that functions as a transporter to move a drug from the blood into heart cells. By introducing another anticancer drug in advance of the chemo, the researchers were able to block the transporter protein, stopping the delivery of doxorubicin to those cardiac cells. This added drug, nilotinib, has been previously found to inhibit activation of other related transport proteins. The current findings are based on lab experiments in cell cultures and mice. The researchers are continuing studies with hopes of soon designing human trials of the drug intervention. “The proposed intervention strategy that we’d like to use in the clinic would be giving nilotinib before a chemotherapy treatment to restrict doxorubicin from accessing the heart,” says first author Kevin Huang, who in December 2020 earned a PhD in pharmaceutical sciences at Ohio State. “We have pretty solid preclinical evidence that this intervention strategy might work.”
The study, published (Jan. 25, 2021) in the journal Proceedings of the National Academy of Sciences, was supported in part by funds from Pelotonia. Huang was named a Pelotonia graduate student fellowship recipient in 2018. Doxorubicin has long been known for its potential to increase patients’ risk for serious heart problems, with symptoms sometimes surfacing decades after chemo, but the mechanisms have been a mystery. The risk is dose-dependent—the more doses a patient receives, the higher the risk for cardiac dysfunction later in life. Huang worked in the lab of senior study authors Shuiying Hu, PhD, and Alex Sparreboom, PhD, faculty members in pharmaceutics and pharmacology and members of the OSUCCC – James Translational Therapeutics Program. This research and other studies targeting transport proteins to prevent chemo-related nerve pain were also part of Huang’s PhD dissertation.
“Our lab works on the belief that drugs don’t naturally or spontaneously diffuse into any cell they would like to. We hypothesize that there are specialized protein channels found on specific cells that will facilitate movement of internal or external compounds into the cell,” Huang says. For this work, the team focused on cardiomyocytes, cells composing the muscle behind the heart contractions that pump blood to the rest of the body. The researchers examined cardiomyocytes that were reprogrammed from skin cells donated by two groups of cancer patients who had been treated with doxorubicin—some who suffered cardiac dysfunction after chemo, and others who did not. The scientists found that the gene responsible for production of the transport protein in question, called OCT3, was highly expressed in the cells derived from cancer patients who had experienced heart problems after treatment with doxorubicin. “We used mouse models and engineered cell models to demonstrate doxorubicin does transport through this protein channel, OCT3,” Huang says. “We then looked prospectively into what this means from a therapy perspective.” Blocking OCT3 became the goal after researchers found that genetically modified mice lacking the OCT3 gene were protected from heart damage after receiving doxorubicin. Further studies showed that inhibiting OCT3 did not interfere with doxorubicin’s effectiveness against cancer. The researchers plan to gather additional supporting evidence before pursuing a phase I clinical trial testing the safety of two components of the proposed drug intervention in humans: blocking the function of the OCT3 transporter protein and demonstrating that inhibiting OCT3 in patients treated with doxorubicin protects those patients’ hearts from chemo -induced injury.