ENJOY SCIENCE Seminar Series
The ENJOY SCIENCE seminar series is open to internal and external colleagues and patients from around the world. Join us on Tuesdays, Thursdays and Fridays, as we highlight the incredible clinical and mechanistic research taking place at MD Anderson.
Connect Science Seminar Series
The Connect Science Seminars seek to connect basic and translational cancer researchers in Houston, Texas, and the nation during the COVID-19 pandemic. This series is open to all, and will showcase outstanding scientists at major institutions in the U.S. and elsewhere every Thursday.
John H. Blaffer Lecture Series
Join us each week from September through May as an internationally recognized scientist presents his or her latest results. The Blaffer Lecture Series is coordinated by MD Anderson's Genetics department.
Researchers at The University of Texas MD Anderson Cancer Center have developed a novel targeted therapy, called POMHEX, which blocks critical metabolic pathways in cancer cells with specific genetic defects. Preclinical studies found the small-molecule enolase inhibitor to be effective in killing brain cancer cells that were missing ENO1, one of two genes encoding the enolase enzyme.
The study results, published today in Nature Metabolism, provide proof of principle for a treatment strategy known as collateral lethality, in which an important protein is lost through genetic deletion as a bystander near a tumor suppressor gene, and a redundant protein is blocked therapeutically.
“Collateral lethality could expand the scope of precision oncology beyond activated oncogenes, and allow targeting of genomic deletions, largely considered un-actionable,” said corresponding author Florian Muller, Ph.D., assistant professor of Cancer Systems Imaging and Neuro-Oncology. “Our work provides proof of principle that this approach can actually work with a drug in animal models.”
Enolase is an essential enzyme involved in glycolysis, a metabolic pathway that is elevated in many cancers to fuel their increased cell growth. Two genes, ENO1 and ENO2, encode slightly different but redundant versions of enolase, and several cancers, such as glioblastoma, are missing the ENO1 gene because of chromosomal loss. This leaves the cancer cells with only ENO2 to continue glycolysis, making them highly sensitive to enolase inhibitors, Muller explained.
Therapies that target both forms of enolase have previously been developed, but blocking ENO1 can have unwanted side effects in normal cells. Targeting ENO2 specifically is attractive because it allows for the selective treatment of cancer cells missing ENO1.
The research team therefore worked to generate an enolase inhibitor, called HEX, that preferentially targets ENO2 over ENO1. To improve the drug’s ability to enter cells, the team created the prodrug POMHEX, which is biologically inactive until it is metabolized into HEX within cells.
In cancer cell lines lacking ENO1, treatment with POMHEX blocked glycolysis, inhibited cell growth and stimulated cell death. Conversely, treatment of cells with normal ENO1 showed minimal effects.
Further, in animal models of ENO1-deficient tumors, both HEX and POMHEX treatment was well- tolerated and effectively blocked tumor growth relative to controls, with some instances of complete tumor eradication. Taking the work one step further, the team demonstrated that the therapeutically effective dose could be safely given in multiple models, suggesting favorable future translation to the clinical studies.
“We were encouraged by the promising preclinical activity of these novel enolase inhibitors and that the safety profile extends to higher models. While there could be further refinements, I am optimistic that even HEX would show significant clinical activity against ENO1-deleted cancers,” Muller said.
ENO1 deletions also occur in liver cancer, bile duct cancer and large-cell neuroendocrine lung cancers, all of which share poor prognosis and limited treatment options, Muller explained. Thus, once an optimal therapy candidate has been developed, there is potential to evaluate the ENO2 inhibitor in treating patients with multiple cancer types.
This research was supported by the National Institutes of Health/National Cancer Institute (CA16672, P30CA016672, P50CA127001-07, 2P50CA127001-11A1, CA225955), the American Cancer Society, the National Comprehensive Cancer Network, the Andrew Sabin Family Foundation, the Dr. Marnie Rose Foundation, the Uncle Kory Foundation, the MD Anderson Institutional Research Grant, and the Cancer Prevention & Research Institute of Texas (RP140612).
In addition to Muller, MD Anderson co-authors on the study include: Yu-Hsi Lin, Naima Hammoudi, Ph.D., Victoria C. Yan, Yasaman Barekatain, Sunada Khadka, Jeffrey J. Ackroyd, Dimitra Georgiou, Ph.D., Cong-Dat Pham, Ph.D., Kenisha Arthur, Federica Pisaneschi, Ph.D., Susana Castro Pando, Xiaobo Wang, and Theresa Tran, all of Cancer Systems Imaging; Nikunj Satani, of Cancer Systems Imaging and UTHealth Institute of Stroke and Cerebrovascular Disease; David Maxwell, Ph.D., of Institutional Analytics & Informatics; Paul G. Leonard Ph.D., Barbara Czako, Ph.D., Pijus Mandal, Ph.D., Quanyu Xu, Ph.D., Qi Wu, Yongying Jiang, Ph.D., and Zhijun Kang, all of the Institute for Applied Cancer Science; Yuting Sun, Ph.D., and Joseph R. Marszalek, Ph.D., of the TRACTION platform; Rafal Zielinski, Ph.D., and Waldemar Priebe, Ph.D., both of Experimental Therapeutics; and Ronald A. DePinho, of Cancer Biology. Additional authors include Zhenghong Peng, Cardtronics, Houston, TX; John M. Asara, Ph.D., Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA; and William Bornmann, Ph.D., Advanced Organic Synthesis LLC, Houston, TX. A full list of author disclosures can be found with the full paper here.
The University of Texas MD Anderson Cancer Center and Obsidian Therapeutics, Inc. today announced a multi-year strategic collaboration designed to expedite the research and development of novel engineered tumor infiltrating lymphocytes (TILs) for the treatment of solid tumors. The agreement pairs Obsidian and its novel cytoDRiVE™ technology platform with MD Anderson’s extensive experience and state-of-the-art capabilities in TIL cell therapy, led by the Biologics Development platform, within the Therapeutics Discovery division.
The collaboration is focused on developing TIL armored with regulated membrane-bound IL15 (referred to as cytoTIL™) with the potential to enhance anti-tumor efficacy and reduce tumor burden in patients suffering from different types of solid tumors. The teams will collaborate to accelerate the development of cytoTIL, including process and analytical development and clinical readiness activities.
“TIL therapy has emerged as a promising option for treating patients with solid tumors, though its widespread use today is limited by safety and efficacy challenges,” said Rodabe Amaria, M.D., associate professor of Melanoma Medical Oncology at MD Anderson. “We are pleased to work with Obsidian to advance their novel cytoTIL program, which has the potential to drive more durable treatment responses and expand TIL therapy to a broader group of our patients.”
The cytoTIL therapy is engineered using Obsidian's cytoDRiVE platform technology, which precisely and reversibly controls protein expression and activity using FDA-approved orally bioavailable drugs. By leveraging regulated membrane-bound IL15 to drive antigen-independent expansion of T cells and transactivation of NK cells, cytoTIL therapy is anticipated to improve patient response to TIL treatment and expand patient eligibility to those who currently cannot benefit from this transformative therapy.
“We are delighted to work with MD Anderson’s Biologics Development team to build upon the success of first generation TIL therapies and bring the first controllable TIL therapy to patients as rapidly as possible,” said Paul Wotton, Ph.D., CEO of Obsidian Therapeutics. “Through its cell therapy research platforms, deep clinical development experience, and industrial manufacturing capabilities, MD Anderson is a best-in-class collaborator to advance and accelerate cutting-edge cell therapies.”
MD Anderson’s Biologics Development
platform is built around an experienced team focused on pioneering
impactful biologic therapeutics, including antibodies and cell
therapies. With a state-of-the-art 60,000 sq. foot GMP cell-therapy
manufacturing facility, the platform joins MD
Anderson expertise with the rigor of industrial development.
Biologics Development offers a strong starting point for early-stage
companies to access the breadth of MD
Anderson capabilities in cell therapy development.
MD Anderson is implementing an Institutional Conflict of Interest Management and Monitoring Plan for any research related to this relationship.
Researchers from The University of Texas MD Anderson Cancer Center have conducted the first randomized clinical trial comparing stereotactic radiosurgery (SRS) to whole brain radiation therapy (WBRT) in patients with four to 15 brain metastases, providing evidence to support the use of SRS in this patient population.
Results from the Phase III trial, led by Jing Li, M.D., Ph.D., associate professor of Radiation Oncology and co-director of MD Anderson’s Brain Metastasis Clinic, were presented today (Abstract 41) at the American Society for Radiation Oncology (ASTRO) Annual Meeting.
Brain metastases are tumors that form when cancer from another part of the body spreads to the brain. SRS is a highly precise form of radiation therapy that treats each brain tumor with a single, targeted high-dose of radiation, delivered in an outpatient setting. WBRT delivers radiation to the entire brain over weeks, and is associated with significant cognitive side effects that negatively impact patients’ quality of life.
Within the last five years, SRS became the standard of care for patients with one to three brain metastases, based on results from randomized clinical trials that demonstrated better cognitive function with no impact to overall survival. Patients with four or more metastatic brain tumors were not included in the earlier trials, and WBRT remained the standard of care for this group, due to concerns about disease control in the brain.
“The number of lesions in the brain is an indicator of the metastatic disease burden in the brain,” Li said. “For example, if a patient has a single brain metastasis, it's likely that's the only site of metastasis in the brain. However, a patient with 10 metastases has a higher risk of also having microscopic tumors that we don't see on MRI scan. Our trial was designed to determine if it’s still appropriate to omit or delay whole brain radiation for these patients. Based on our data, stereotactic radiosurgery helps patients preserve their cognitive functions, as compared to whole brain radiation therapy, without causing any difference in the overall survival.”
Stereotactic radiosurgery preserves cognition without compromising overall survival
The study opened in 2012 and enrolled 72 patients. Trial participants were 83% Caucasian, 8% Black, 6% Hispanic and 3% Asian. Nearly half of the participants (35) were age 60 or older, and 58% were female. Based on the results of a different phase III trial (RTOG 0614) that published in 2013, 62% of patients in the WBRT arm also received memantine, a dementia drug that helps preserve cognitive function.
Participants had a median of eight brain metastases and were randomized to receive WBRT or SRS. They completed neurocognitive testing, including learning, memory, attention span, executive function, verbal fluency, processing speed and motor dexterity, at enrollment and longitudinally.
Four months after radiation therapy, patients in the SRS group scored higher on a memory function test than those who received WBRT (average z-score change from patient’s own baseline, +0.21 for SRS and -0.74 for WBRT; p=0.04). Far more patients in the WBRT arm (50%) experienced a clinically meaningful decline in cognitive function, than the SRS arm (6%).
Overall survival did not differ between the groups (SRS median 7.8 months, WBRT median 8.9 months, p=0.59). SRS resulted in better local control rates (95% at four months with SRS and 86.7% with WBRT, p=0.09), but shorter median time to distant brain failure (10.5 months for WBRT and 6.3 months for SRS, p=0.37). Patients in the SRS arm also experienced shorter interruptions of systemic therapy (SRS median time to systemic therapy 1.7 weeks, WBRT 4.1 weeks, p=0.001). Grade 3 or higher toxicities were observed in four patients in the WBRT arm and two in the SRS arm.
“Patients receiving stereotactic radiosurgery need to be closely monitored with brain re-imaging every three months so any new tumors can be caught and treated when they are small,” Li said. “In the end, patients do not have increased risk of dying from managing the recurrent disease with salvage treatment, and they get to enjoy having better cognitive function.”
Despite enrollment challenges, data supports the use of SRS for this patient population
The trial was terminated early after enrolling 72 patients, due to the publication of another phase III trial (NRG Oncology CC 001) that provided level 1 evidence for replacing standard WBRT with hippocampal avoidance WBRT.
“Despite early closure of the study, we were pleased to see such strong signals in our data with neurocognitive benefit associated with SRS,” Li said. “We are extremely grateful to the patients and families who participated in our trial and made this progress possible. Our next steps are to compare stereotactic radiosurgery with hippocampal avoidance WBRT to determine which treatment option provides the most benefit, and also to investigate how SRS can be combined with systemic therapy to further improve treatment outcomes of patients with brain metastases.”
A full list of co-authors and their disclosures can be found here.