Ohio State-Developed Drug Receives FDA Approval for Treating CLL, SLL
On Nov. 21, 2019, the U.S. Food and Drug Administration (FDA) approved the use of the drug acalabrutinib for first-line therapy in chronic lymphocytic leukemia (CLL) and small cell lymphoma (SLL).
It was the first full approval of this targeted drug therapy, which was developed and tested at the OSUCCC – James in collaboration with the pharmaceutical partner Acerta Pharma.
Acalabrutinib, marketed as Calquence®, is a second-generation Bruton tyrosine kinase (BTK) inhibitor, a newer class of drugs shown to improve the survival of patients with mantle cell lymphoma in addition to CLL and SLL.
The drug works by permanently binding BTK, which is part of a chain of proteins that relays growth signals from the surface of the cancer cell to genes in the cell nucleus, enabling cancer cells to survive and grow. By blocking BTK, the drug halts the flow of these growth signals, and the cancer cells die.
Unlike the first generation BTK inhibitor (ibrutinib, marketed as IMBRUVICA®), preclinical and clinical data shows that acalabrutinib more selectively blocks the BTK pathway without disrupting other key molecular pathways that are important for preserving platelet and immune function, thereby preventing/minimizing certain side effects associated with cancer treatment.
The foundational basic-science research, initial phase I clinical trial and numerous sequential phase II and phase III clinical trials that led to this new FDA approval of acalabrutinib were performed by a team of researchers at the OSUCCC – James led by John C. Byrd, MD, a Distinguished University Professor at Ohio State and co-leader of the Leukemia Research (LR) Program at the OSUCCC – James. Byrd also holds the D. Warren Brown Designated Chair of Leukemia Research in the College of Medicine.
This research included collaborative clinical trials with Ohio State’s College of Veterinary Medicine and the Comparative and Translational Oncology Program, a research collaboration that integrates nearly 40 scientific investigators from Ohio State’s colleges of medicine, pharmacy, nursing and veterinary medicine, along with researchers from Nationwide Children’s Hospital, to investigate cancers that occur in both humans and animals. William Kisseberth, DVM, PhD, a professor in the Department of Veterinary Clinical Sciences, directed the studies of acalabrutinib in dogs with lymphoma.
“Acalabrutinib is a highly potent and selective oral BTK inhibitor that has proven to be very effective for our patients affected by CLL and other blood cancers. It is remarkably well tolerated and results in longer progression-free survival. We are honored and thrilled that this research is helping patients thrive,” says Byrd.
Collaborator Jennifer Woyach, MD, associate professor in the Division of Hematology and member of the LR Program, presented study data at the 2019 American Society of Hematology (ASH) annual meeting on the mechanisms of resistance that cause some patients to stop responding to acalabrutinib.
Study Suggests New Strategy for Treating Advanced, Progressing Bile Duct Cancer
A study led by OSUCCC – James researchers shows how resistance to a promising targeted drug develops in patients with a rare, lethal cancer of the bile ducts called cholangiocarcinoma.
Reported in the journal , the study also suggests that adding another drug when the cancer starts to progress might re-sensitize tumor cells to the initial drug, which is called an FGFR inhibitor because it thwarts the action of the FGFR gene. (FGFR stands for fibroblast growth factor receptor).
“While most patients with FGFR-positive cholangiocarcinoma benefit from new FGFR inhibitors in clinical trials, most patients unfortunately develop cancers resistant to the drugs,” says study leader Sameek Roychowdhury, MD, PhD, a medical oncologist and researcher at the OSUCCC – James. “We believe this study is an important step in understanding drug resistance and improving the treatment of this and other cancers caused by FGFR gene mutations.”
Findings also suggest that monitoring fragments of circulating tumor DNA for acquired mutations that cause resistance to FGFR inhibitors may reveal the presence of resistance mutations and mark the time a patient should begin taking the additional drug, which is known as an mTOR inhibitor.
The successful treatment of cholangiocarcinoma is challenging because the disease is usually diagnosed at an advanced stage that has a five-year survival rate of 2%. Patients diagnosed earlier also have low five-year survival due to high rates of disease recurrence. Abnormal activation of the FGFR gene occurs in 15-20% of patients with cholangiocarcinoma, and FGFR inhibitors show effectiveness in 70-80% of those patients until resistance develops. FGFR inhibitors are being studied in several clinical trials at the OSUCCC – James.
“Having a better understanding of how treatment resistance develops and how to prevent it is critical for improving the treatment of cholangiocarcinoma and other cancers caused by FGFR mutations,” says Melanie Krook, PhD, a postdoctoral fellow in Roychowdhury’s lab who was first author on the published study.
“Our findings suggest that cholangiocarcinoma patients treated with an FGFR targeted therapy could benefit from combination therapies with other drugs such as mTOR inhibitors. Additional laboratory studies are needed to identify optimal lead strategies for this combination,” she adds.
For this study, Roychowdhury, Krook and colleagues examined the FGFR gene in the cancer cells of a cholangiocarcinoma patient who died after experiencing disease progression and developing resistance to the FGFR inhibitor drug known as infigratinib.
The researchers identified two acquired FGFR mutations in the patient’s tumor cells that conferred resistance to FGFR inhibitors. They then used cancer cell lines to learn that the mutations led to activation of the mTOR biochemical pathway. This enabled the cancer cells to grow, even in the presence of FGFR inhibitors. However, adding an mTOR inhibitor to the cells restored their sensitivity to FGFR inhibitors.
Blocking Fat Storage May Offer New Way of Treating Most Lethal Form of Brain Cancer
Glioblastoma (GBM) is a lethal brain cancer that accumulates fats in lipid droplets and uses them as energy for rapid cell division. Blocking an enzyme that GBM cells use to form the lipid droplets might offer a new way to treat this deadly disease, according to a study led by researchers at the OSUCCC – James.
GBM has an average survival of 12-15 months after diagnosis, a period that has remained unchanged for two decades. New and more effective treatments are desperately needed.
In earlier work, this same research team learned that GBM cells accumulate unusually high levels of fatty acids and use them as a source of energy needed for rapid cell growth. Normally, excessive levels of fatty acids are deadly to cells.
In this study, published in the journal Cell Metabolism, the researchers looked at an enzyme called DGAT1 (diacylglycerolacyltransferase 1). GBM cells use the enzyme to package fatty acids into lipid droplets. The enzyme converts fatty acids into molecules called triglycerides, which can be safely stored as lipid droplets in the cancer cells’ cytoplasm.
But blocking DGAT1 diverted the excessive fatty-acid molecules to mitochondria, the cells’ energy-producing organelles, rather than to storage. This overwhelmed the organelles, causing them to produce high levels of destructive molecules called oxygen radicals (also called reactive oxygen species). This, in turn, damaged the mitochondria and triggered the cells to self-destruct through a process called apoptosis.
“These findings suggest that inhibiting DGAT1 might offer a new therapeutic approach for the treatment of glioblastoma,”says principal investigator Deliang Guo, PhD, professor in the Department of Radiation Oncology and director of Center for Cancer Metabolism at Ohio State, where he also is in the Translational Therapeutics Program at the OSUCCC – James.
“This same approach might also apply to cancers such as prostate, colon, renal and others, which also show lipid-droplet formation,” says Guo. For this study, Guo and colleagues analyzed patient tumor tissue, multiple GBM cell lines and an animal model to examine fatty acid metabolism and lipid droplet formation in GBM.
“Overall,” Guo says, “our findings may lead to the identification of lipid-metabolism pathways that are unique to glioblastoma and other malignancies, and to new therapies for these cancers.”
Study May Refine Diagnosis and Treatment of Younger Adults With Acute Leukemia
The findings of a study led by researchers at the OSUCCC – James could refine an important set of diagnostic and treatment recommendations for middle-aged patients with acute myeloid leukemia (AML).
The retrospective study evaluated the molecular characteristics and outcomes of 863 AML patients under age 60 who were treated according to 2017 European LeukemiaNet (ELN) recommendations. The ELN is a European Union-funded organization of physicians, scientists and patients who focus on leukemia. The Ohio State University joined LeukemiaNet in 2014.
ELN recommendations are internationally used for diagnosing and managing people with AML and other leukemias. AML is a blood cancer that affects 19,900 Americans and kills nearly 11,200 of them yearly, according to the American Cancer Society. The OSUCCC – James researchers note that only 35-40% of AML patients under age 60 achieve long-term survival.
This study, published in the journal Leukemia, found that 9% of favorable-risk and 53% of intermediate-risk patients should be reclassified as adverse risk, and that 4% of favorable-risk and 9% of adverse-risk patients should be reclassified as intermediate risk.
“If verified, our findings may refine the ELN risk stratification of younger AML patients, which could improve their treatment choices and outcomes,” says corresponding author Ann-Kathrin Eisfeld, MD, an investigator in the OSUCCC – James Leukemia Research Program.
During this study, Eisfeld and her colleagues detected 2,354 mutations, an average of three per patient (median age 45 years). They also determined the frequency of current ELN risk group-defining mutations, additional mutations that differed among the risk groups, and mutations in three “functional group” categories: RAS-pathway mutations, kinase and methylation-related mutations, and mutations in genes encoding for spliceosomes, transcription factors and tumor suppressors.
The researchers compared the frequencies of the mutations within each ELN risk group — favorable, intermediate and high — to learn which were associated with better or worse outcomes and might therefore help refine the 2017 ELN classification.
The research paper stemming from this study is dedicated to the memory of its senior author, Clara D. Bloomfield, MD, who died in March 2020 during completion of the manuscript. Bloomfield, a Distinguished University Professor at Ohio State who also served as cancer scholar and senior adviser to the OSUCCC – James, was instrumental in developing the 2017 ELN recommendations, which replaced those that were issued by the ELN in 2010 that were also co-authored by Bloomfield.