Ohio State Cancer Study Called ‘Key Breakthrough and Insight for 2015’

The American Cancer Society (ACS) featured a study by researchers at the OSUCCC – James as one of “10 key breakthroughs and insights for 2015.” The study, “Glucose- Mediated N-glycosylation of SCAP is Essential for SREBP-1 Activation and Tumor Growth,” was published in the journal Cancer Cell. The researchers identified a key pathway used by cancer cells to make lipids (fats) by integrating oncogenic signaling, fuel availability and lipid synthesis to support cell division and rapid tumor growth. They found a molecule in that pathway that, if blocked, could cripple lipid production by cancer cells and slow tumor growth—a possible new strategy for treating a lethal brain cancer called glioblastoma multiforme and other malignancies. Principal investigator was Deliang Guo, PhD.

Researchers Contribute to ASCO’S Choice for ‘Cancer Advance of the Year’

OSUCCC – James scientists played a key role in some of the recent research that has helped transform treatment for chronic lymphocytic leukemia (CLL)—a transformation that the American Society of Clinical Oncology (ASCO) called the “Cancer Advance of the Year” for 2015. ASCO’s Clinical Cancer Advances 2015 noted that four new therapies, including two targeted drugs and two immunotherapies, had been approved by the U.S. Food and Drug Administration in just a year’s time for CLL, the most common form of adult leukemia. Much of the research leading to approval of the drug ibrutinib, one of the two targeted agents, was performed by scientists at the OSUCCC – James, including John C. Byrd, MD, Amy J. Johnson, PhD, and several others.

Breast Study Highlighted as Breaking Advance in Cancer Literature

A study led by researchers at the OSUCCC – James and published in the journal Cancer Research was selected by that journal for inclusion in “Breaking Advances: Highlights From Recent Cancer Literature,” a compendium of articles from many prestigious journals. Ramesh Ganju, PhD, was corresponding author for the study. The Breaking Advances citation, written by Cancer Research editors, says the OSUCCC – James study reveals how RAGE (receptor for advanced glycation end products), a multifunctional receptor associated with inflammation and cancer, contributes to breast cancer progression and metastasis. In the study abstract, the scientists report that RAGE expression is widely upregulated in aggressive triple-negative breast cancer (TNBC) cells, both in primary tumors and lymph node metastases. Overall, their results highlight RAGE as a candidate biomarker and therapeutic target for TNBC.

Genetic Biomarker May Predict Patients’ Response to Immunotherapy Drug

Changes that knock out genes involved in the repair of damaged DNA might predict which patients will respond to certain immunotherapy drugs, according to data from a study co-authored by scientists at the OSUCCC – James and published in the New England Journal of Medicine. The finding comes from an ongoing phase II trial examining the effectiveness of the drug pembrolizumab. Richard Goldberg, MD, is principal investigator of the local arm of this national trial and a co-author of the study. Defects in these so-called “mismatch repair genes” were originally discovered in 1993 by a team that included Albert de la Chapelle, MD, PhD. Mutations in mismatch repair genes occur in both sporadic and hereditary forms of colorectal, endometrial (uterine), stomach, biliary tract, pancreatic, ovarian and small intestine cancer.

Studies Suggest Ways to Inhibit Oncogenes, Enhance Tumor-Suppressor Activity

Two studies by scientists at the OSUCCC – James suggest new approaches for treating cancer by inhibiting overactive cancerpromoting genes and by enhancing the activity of sluggish tumor-suppressor genes. The findings were reported in the journals Nature Communications and Nature Genetics. Principal investigator for both studies was Qianben Wang, PhD. The Nature Communications paper focused on oncogenes that are activated by dexamethasone-bound glucocorticoid receptor (GR) in triple-negative breast cancer (TNBC). This study combined extensive genomic datasets in TNBC cells and breast cancer gene expression datasets from more than 2,000 patients. The Nature Genetics study, jointly supervised by Wang and a second principal investigator, Wei Li, PhD, of Baylor College of Medicine, focused on tumor-suppressor genes, which normally protect cells from becoming cancerous. The work suggested that tumor-suppressor activity might be enhanced in cancer cells by prolonging a step in the gene-expression process called the transcription-elongation phase.

Researchers Detail Reasons for Ibrutinib Discontinuation in CLL

About 10 percent of patients with chronic lymphocytic leukemia (CLL) discontinued therapy with the Bruton’s tyrosine kinase (BTK) inhibitor drug known as ibrutinib because of disease progression during clinical trials, according to a study at the OSUCCC – James that was published in the journal JAMA Oncology. Kami Maddocks, MD, was first author on the study, and Jennifer Woyach, MD, was senior author. Ibrutinib (marketed as Imbruvica®) is the first drug designed to target BTK, a protein essential for CLL-cell survival and proliferation. The drug is approved by the U.S. Food and Drug Administration (FDA) for treating certain patients with CLL and mantle cell lymphoma. Much of the clinical and basic-science research that led to FDA approval was performed by scientists at Ohio State.

Study Supports IDH Gene as Prognostic in Rare Brain Cancer

New findings suggest that a gene called IDH might be a prognostic marker for a rare form of brain cancer called anaplastic astrocytoma. Patients in this study, part of the multi-institutional phase III clinical trial RTOG 9813, who had a mutated IDH gene lived an average of 7.9 years after diagnosis versus 2.8 years for patients with unaltered IDH. Some 300 patients were involved in the dual-arm trial, which evaluated the efficacy of radiation therapy plus either of two chemotherapy drugs: temozolomide and nitrosourea. Arnab Chakravarti, MD, of the OSUCCC – James, was the trial’s translational research national study chair and a coauthor of the findings, which were presented at the 2015 meeting of the American Society of Clinical Oncology.

CanDL Database Shines Light on Clinically Important Cancer Gene Mutations

Many clinical trials use genome sequencing to learn which gene mutations are present in a patient’s tumor cells. This is important because targeting the right mutations with the right drugs can stop cancer in its tracks. But it can be difficult to determine whether there is evidence in the medical literature that particular mutations might drive cancer growth and could be targeted by therapy, and that other mutations might be of no consequence. To help molecular pathologists, laboratory directors, bioinformaticians and oncologists identify key mutations that drive tumor growth in tissues obtained in clinical studies, researchers led by principal investigator Sameek Roychowdhury, MD, PhD, have designed a freely accessible online database called the Cancer Driver Log (CanDL).

Oncologists Should Use Dual-Delivery Treatment More Often for Ovarian Cancer

Less than half of ovarian cancer patients eligible for a combined chemotherapy regimen that can significantly improve survival actually receive it, according to a study authored by researchers from six leading cancer centers, including the OSUCCC – James. This study was the first outside of a clinical trial to analyze whether chemotherapy delivered using two routes—one into the abdomen, or intraperitoneally (IP), and the other intravenously (IV)—can improve survival in women with stage III ovarian cancer after surgery to remove the tumor. The researchers reported their findings in the Journal of Clinical Oncology. David O’Malley, MD, of the OSUCCC – James, served as senior author of the study.

Study Shows Potential for Immunotherapeutic Strategy Against Lung Cancer

A preclinical multi-institutional study co-led by researchers at the OSUCCC – James supports the development of a molecular strategy to stimulate the body’s antitumor immunity in lung cancer and improve the effectiveness of therapy that targets lung tumors containing EGFR gene mutations. Mikhail Dikov, PhD, was a cocorresponding author for the study, which was published in the journal Cancer Research. David Carbone, MD, PhD, was a coauthor. The study involved manipulating interaction between Notch proteins, which help regulate cellular processes and immune responses, and a Notch receptor molecule called DLL1 in mouse models of human lung cancer. Researchers found that activating Notch signaling using clustered DLL1, combined with a drug (erlotinib) that targets EGFR gene mutations, significantly improved progression-free survival in the mice—offering preclinical support for the development of multivalent DLL1 to stimulate antitumor immunity.

Study Rejects Biologic Age as Limiting Factor for Stem Cell Transplants

More than 40 percent of older patients with acute myeloid leukemia (AML) can remain in long-term cancer remission through a modified, less aggressive approach to donor stem cell transplantation, according to the results of a phase II multicenter study led by oncologists at the OSUCCC – James. Steven Devine, MD, led the study, which was published in the Journal of Clinical Oncology. AML is an aggressive blood cancer that is life threatening and is typically diagnosed in patients older than 60. The data represents new hope in a disease where the five-year survival rate is often below 10 percent, despite achieving initial remission. “This new data offers strong support against using biological age as a limiting factor for stem cell transplantation in AML patients who are otherwise well positioned to tolerate and achieve long-term remission with this approach,” says Devine, principal investigator of the national clinical trial.

‘Nanobombs’ Might Deliver Agents That Alter Gene Activity in Cancer Stem Cells

Researchers at the OSUCCC – James have developed nanoparticles that swell and burst when exposed to near-infrared laser light. Such “nanobombs” might overcome a biological barrier that has blocked development of agents that work by altering the activity of genes in cancer cells. The agents might kill cancer cells outright or stall their growth. Xiaoming (Shawn) He, PhD, was principal investigator for this study, published in the journal Advanced Materials. He and colleagues used human prostate cancer cells and human prostate tumors in an animal model. The nanoparticles were equipped to target cancer stem-like cells (CSCs), which are cancer cells that have properties of stem cells. CSCs often resist therapy and are thought to play an important role in cancer development and recurrence. The therapeutic agent in the nanoparticles was a form of microRNA called miR-34a.

Experimental Drug May Prevent Life-Threatening Muscle Loss in Cachexia

New data describes how an experimental drug can stop lifethreatening muscle wasting (cachexia) associated with advanced cancers and restore muscle health. The experimental agent, known as AR-42 while in testing, was developed and tested in preclinical studies at the OSUCCC – James. Corresponding authors for the study, published in the Journal of the National Cancer Institute, were Tanios Bekaii-Saab, MD, and Ching-Shih Chen, PhD. AR-42, developed in Chen’s lab, is part of a class of drugs known as histone deacetylase (HDAC) inhibitors, which are designed to block proteins that help mediate skeletal muscle breakdown. HDAC proteins also tend to drive the pathways in cancer cells that lead to aggressive malignancies. AR-42 is unique among HDAC inhibitors because it appears to have beneficial effects on muscle health and function.

Drug Shows Potential as Safe and Effective for Treating CLL

Clinical results published in the New England Journal of Medicine show that the new drug acalabrutinib (ACP-196) promotes high response rates that are durable in patients with chronic lymphocytic leukemia (CLL) while producing minimal side effects. The preclinical and clinical efforts for this project reported with ACP-196 were led by John C. Byrd, MD, and Amy J. Johnson, PhD. ACP-196, a second-generation Bruton’s tyrosine kinase (BTK) inhibitor, works by permanently binding BTK, which is part of a chain of proteins that relays growth signals from the surface of CLL cells to genes in the cell nucleus, enabling cancer cells to survive and grow. By blocking BTK, the drug halts these growth signals, and the CLL cells die. Data reported in this study suggests that, unlike the first-generation BTK inhibitor (ibrutinib), acalabrutinib more selectively blocks the BTK pathway without disrupting other pathways important for preserving platelet and immune function, thereby preventing/minimizing some side effects associated with cancer treatment.

Tumor DNA Testing Can Improve Lynch Syndrome Testing at Any Age

Research at the OSUCCC – James suggests that many cases of Lynch syndrome could go undetected with current recommendations for age restrictions and testing methods. Lynch syndrome is an inherited genetic condition that predisposes mutation carriers to certain cancers, most commonly colorectal and endometrial (uterine), but also ovarian, stomach and other gastrointestinal tract cancers. In this study, published in the Journal of Clinical Oncology, researchers show that 24 percent of Lynch syndrome mutation carriers were diagnosed with endometrial cancer over age 60; however, it has been recommended that tumor studies to screen for Lynch syndrome be limited to patients 60 or younger. As a result of this data, researchers encourage Lynch syndrome testing in all newly diagnosed endometrial cancer patients regardless of age. Paul Goodfellow, PhD, was corresponding author for this study.

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