December 18, 2015 | by City of Hope
by Chase Doyle
Sometimes, just a few remaining cancer cells can mean the difference between remission and relapse. For patients with aggressive bone marrow disease such as acute myeloid leukemia (AML), this distinction can be deadly.
City of Hope researchers are determined to eliminate those remaining cancer cells and, in doing so, improve patient survival. First, however, they must understand how resistance works.
According to a new study featured on the cover of the journal Cell Stem Cell, they’re closer than ever to their ultimate goal – and are now exploring a potential new approach in the fight against AML.
“That’s the challenge in AML treatment,” said Ya-Huei Kuo, Ph.D., associate professor of the Division of Hematopoietic Stem Cell and Leukemia Research at Beckman Research Institute of City of Hope. “Patients can receive chemotherapy treatment and go into remission, but if there are just a few leukemia stem cells left behind, a relapse can occur, and relapses tend to be resistant to the initial therapy.”
by Elise Lamar
Cancer researchers increasingly realize that drug combinations, as opposed to single drugs, may be the best treatment approach. If so, some are asking, why not use entirely different treatment regimens to create the ultimate weapon against tumors? City of Hope researchers are addressing that possibility by combining two approaches at which they excel – bone marrow transplant and immunotherapy – as a way to treat recurrent blood cancers.
As a first step, they reported success of a relevant phase 1 safety trial at the annual meeting of the American Society of Hematology (ASH), held in December in Orlando. There, City of Hope hematologist Leslie Popplewell, M.D., the trial’s principal investigator, reported outcomes following treatment of patients with recurrent non-Hodgkin lymphoma. The patients first received a bone marrow transplant and then, two days later, an infusion of their own genetically modified T cells, an immunotherapy procedure called adoptive cell transfer. The treatment proved safe overall, and many patients participating in the trial are still being monitored for treatment efficacy.
By City of Hope
Steven Rosen, M.D., provost and chief scientific officer of City of Hope, received a Lifetime Achievement Award from the Israel Cancer Research Fund (ICRF) on Nov. 18 at a Chicago gala attended by hundreds of supporters of cancer research. The award recognizes Rosen’s longstanding commitment to advancing science and medicine and providing extraordinary patient care.
“This Lifetime Achievement Award is a remarkable honor, especially coming from the ICRF, an organization that advances scientific understanding of cancer and supports innovations that are transforming lives,” said Rosen, the Irell & Manella Cancer Center Director’s Distinguished Chair. “I am extremely proud, and humbled, to be the recipient of such an honor."
By City of Hope
Two leading City of Hope researchers have received a National Institutes of Health grant to investigate a long-held view that environmental factors could incite the development of breast cancer. An intriguing twist of their research, however, is that when a woman is in menopausal transition, it may increase the probability of developing the disease due to environmental pollutants.
“We believe that during this time, when natural hormone levels are declining, environmental endocrine-disrupting chemicals promote hormone-responsive breast cancers,” said Shiuan Chen, Ph.D., professor and chair of the Department of Cancer Biology. Chen and Susan L. Neuhausen, Ph.D., The Morris & Horowitz Families Professor in Cancer Etiology & Outcomes Research, are co-principal investigators on the study.
The five-year, $4.8 million grant will examine the possible role of environmental exposure in the development of breast cancer during this time of menopausal transition in women.
By Sarah Shuck
For the millions of individuals worldwide with diabetes, the development of complications associated with this disease greatly diminishes quality of life and increases the risk of mortality. One of the most comprehensive diabetic clinical trials, the Diabetes Control and Complications Trial (DCCT), and its follow-up, the Epidemiology of Diabetes Interventions and Complications (EDIC) observational study, found that aggressive glycemic control decreased the progression of vascular complications in type 1 diabetic patients. A major caveat to this study, however, is that type 1 diabetic patients undergoing conventional glycemic control that are switched to more intensive interventions still remain at a higher risk of developing diabetic complications.
Understanding the molecular mechanisms involved in the development of complications in the described cohort is the focus of an intriguing $2.2 million grant awarded to Rama Natarajan, Ph.D., professor and chair of the Department of Diabetes Complications and Metabolism. Natarajan is a preeminent investigator of the molecular mechanisms involved in the development of metabolic memory in cells, one of the mechanisms hypothesized to play a role in the observed outcomes in the EDIC study. Metabolic memory is a process in which prior exposure to altered metabolism, such as high glucose levels, can cause long-lasting changes in cellular function. Natarajan, the National Business Products Industry Professor in Diabetes Research, hypothesizes that epigenetics play a key role in the development of metabolic memory, specifically through DNA methylation and histone modifications. Regarding the latter, Natarajan and her team have recently analyzed samples from the EDIC cohort and demonstrated alterations in histone modifications that may play a role in the development of diabetic complications. They are now extending these studies to investigate DNA methylation in a large number of genomic DNA samples collected during the DCCT trial.
Epigenetic regulation is an emerging area of study with extensive potential for application in numerous disease states, including the establishment of metabolic memory in diabetes. Using innovative and established biochemical approaches, Natarajan will investigate these intriguing relationships, shedding light on this significant factor involved in the development of diabetic complications.
By Sarah Shuck
Despite overcoming tremendous obstacles to beat childhood cancer, these patients retain an increased risk for developing heart failure, particularly following treatment with anthracyclines. Cardiotoxicity induced by this class of drugs is thought to occur through direct injury to the heart, which, over time, results in left ventricular dysfunction. Clinical intervention through administration of beta blockers is proposed to prevent the development of this cardiac dysfunction and is the focus of the proposal awarded to Saro Armenian, D.O., M.P.H., associate professor in the departments of Pediatrics and Population Sciences.
With this $3.1 million grant, Armenian will examine how treatment with the beta blocker carvedilol impacts cardiac failure in childhood cancer survivors previously exposed to anthracyclines. To define this role, he will identify how treatment affects cardiac remodeling and function. In addition, he will also determine the efficacy and safety of this drug.
As treatments for childhood cancers have advanced and led to increased survival, the development of secondary disorders has become a pressing issue. The work outlined by Armenian will provide novel insight into this area of investigation and holds exciting promise for the prevention of heart failure in survivors treated with anthracyclines. In addition, these studies may have application to those treated for breast cancer, sarcoma and lymphoma, to reduce the risk of heart failure in these patients as well.
By Sarah Shuck
Tumor-specific chemotherapeutic targeting of brain tumors is a major obstacle for the oncology research community and the focus of a recent R01 awarded to Jana Portnow, M.D., associate clinical professor in the Department of Medical Oncology and Therapeutics and Karen Aboody, M.D., professor in the Department of Developmental and Stem Cell Biology and Division of Neurosurgery. Their novel approach utilizes neural stem cells (NSCs) that contain therapeutic transgenes to activate chemotherapeutics specifically at brain tumor
They initially demonstrated the utility of this technology in a first-in-human study using cytosine deaminase-expressing NSCs, which resulted in localized conversion of the inactive prodrug 5-flurocytosine (5-FC) to the active chemotherapeutic agent 5-flurouracil (5-FU) in the brains of patients with recurrent high grade gliomas. The findings from that first study demonstrated that intracranially administered NSCs migrated to the tumor sites and produced 5-FU when patients took 5-FC orally. There was no development of anti-NSC immunological response or secondary tumors. These results laid the foundation for the current research proposal which will assess the ability of the NSCs, which have been engineered to express a modified human form of carboxylesterase (CE), that converts the prodrug irinotecan to its more potent metabolite, SN-38, which is 1000x more toxic to tumor cells than irinotecan alone.
Pre-clinical work demonstrating efficacy and safety of intracranially administered CE-expressing NSCs in combination with intravenous irinotecan has led to the development of a phase I clinical trial to investigate this NSC-based treatment strategy in patients with recurrent high grade gliomas. This study will determine the optimal drug concentrations required for use in a phase II clinical trial, assess for possible immunogenicity of this treatment, and measure the extent of conversion of irinotecan to SN-38 in the brain by the NSCs. The cost of this study will be covered by the NIH R01 grant. Demonstration of the feasibility and efficacy of this treatment approach presents a tremendous opportunity to try to improve the outcome for patients with brain tumors.
Results of the proposed study could potentially be applicable to the treatment of other types of brain tumors as well as systemic solid tumor metastases. Aboody currently has a U-01 grant to apply this same therapeutic strategy to children with metastatsic neuroblastoma by 2018.
By City of Hope
Jeffrey Weitzel, M.D., director of Division of Clinical Cancer Genetics in the Department of Population Sciences, and Arti Hurria, M.D., director of the Cancer and Aging Research Program, were each awarded $250,000 by the Breast Cancer Research Foundation (BCRF) to continue their studies to improve treatment and outcomes for older women and for Latino women at risk of hereditary breast cancer.
This is the fourth year that the BCRF has funded Hurria’s efforts to understand the effects of chemotherapy on older adults with breast cancer. The study aims to evaluate cognitive differences between breast cancer patients who receive chemotherapy, those patients who do not, and healthy women of the same age who have never had cancer. The goal is to understand how breast cancer and treatment impact older patients and help inform treatment decisions.
According to Weitzel’s research, as many as 25 percent of women in Latin America and Mexico may have BRCA mutations, which greatly increase their risk of breast and ovarian cancers. This third year of funding from BCRF will allow Weitzel to continue his international project studying BRCA mutations among Latin American women. Weitzel and his team are developing and testing low cost genetic assays that can detect BRCA mutations in this population. They are also using these funds to train clinicians and develop a system of genetic testing and counseling for this population at risk.
By City of Hope
Dan Raz, M.D., co-director of the Lung Cancer and Thoracic Oncology Program, has received The V Foundation for Cancer Research’s V Scholar Award, which recognizes rising stars in the cancer field. The award funding will enable Raz to continue research to find innovative treatments for lung cancer, which is the most common cause of cancer death among men and women in the United States and worldwide.
Raz researches new treatments for lung cancer that target the Wnt signaling pathway, which is involved in normal cell growth, but is also implicated in lung cancer development, progression and metastasis. The V Foundation’s $200,000 award will help fund research that aims to block the Wnt pathway through chemically modifying DNA or DNA packaging proteins known as histones. This new method of blocking this pathway has shown promise in studies performed in Raz’s laboratory.