Leading Edge of Cancer Research Symposium
This symposium will discuss emerging concepts across the breadth of cancer research from cancertherapeutics to immuno-genetics. The event is offered at no charge and is open to research colleagues worldwide.
Genetics of Hereditary Cancer Symposium
Honoring Louise C. Strong, M.D.
Tuesday, June 22, 2021
9 a.m. – 1 p.m. CDT
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 discovered a novel function for the metabolic enzyme medium-chain acyl-CoA dehydrogenase (MCAD) in glioblastoma (GBM). MCAD prevents toxic lipid buildup, in addition to its normal role in energy production, so targeting MCAD causes irreversible damage and cell death specifically in cancer cells.
The study was published today in Cancer Discovery, a journal of the American Association for Cancer Research. Preclinical findings reveal an important new understanding of metabolism in GBM and support the development of MCAD inhibitors as a novel treatment strategy. The researchers currently are working to develop targeted therapies against the enzyme.
“With altered metabolism being a key feature of glioblastoma, we wanted to better understand these processes and identify therapeutic targets that could have real impact for patients,” said lead author Francesca Puca, Ph.D., instructor of Genomic Medicine. “We discovered that glioblastoma cells rely on MCAD to detoxify and protect themselves from the accumulation of toxic byproducts of fatty acid metabolism. Inhibiting MCAD appears to be both potent and specific in killing glioblastoma cells.”
To uncover metabolic genes that are key to GBM survival, the research team performed a functional genomic screen in a unique preclinical model system that permitted an in vivo study using patient-derived GBM cells. After analyzing 330 metabolism genes in this model, they discovered that several enzymes involved in fatty acid metabolism were important for GBM cells.
The team focused on MCAD because it was identified in multiple GBM models and found at high levels in GBM cells relative to normal brain tissue. In-depth studies determined that blocking MCAD in GBM cells resulted in severe mitochondrial failure caused by the toxic buildup of fatty acids, which normally are degraded by MCAD.
This resulted in a catastrophic and irreversible cascade of events from which GBM cells could not recover, explained senior author Andrea Viale, M.D., assistant professor of Genomic Medicine.
“It appears that the downregulation of this enzyme triggers a series of events that are irreversible, and the cells are poisoned from the inside,” Viale said. “Usually, tumor cells are able to adapt to treatments over time, but, based on our observations, we think it would be very difficult for these cells to develop resistance to MCAD depletion.”
While blocking MCAD appears to be detrimental to the survival of GBM cells, the research team repeatedly found that normal cells in the brain were not affected by loss of the enzyme, suggesting that targeting MCAD could be selective in killing only cancer cells. Supporting this observation is the fact that children and animals born with an MCAD deficiency are able to live normally with an altered diet.
“It has become clear that MCAD is a key vulnerability unique to glioblastoma, providing us a novel therapeutic window that may eliminate cancer cells while sparing normal cells,” said senior author Giulio Draetta, M.D., Ph.D., chief scientific officer and professor of Genomic Medicine. “We are looking for discoveries that will have significant benefits to our patients, and so we are encouraged by the potential of these findings. We are actively working to develop targeted therapies that we hope will one day provide an effective option for patients.”
The research team has characterized the three-dimensional structure of the MCAD protein in a complex with novel small molecules designed to block the activity of the enzyme. As promising drug candidates are discovered, the researchers will work in collaboration with MD Anderson’s Therapeutics Discovery division to study these drugs and advance them toward clinical trials.
A full list of collaborating authors and their disclosures can be found here. The research was supported by the National Cancer Institute (NCI) (R01 CA218139 01 A1, R37CA237421, R01CA248160, R01CA244931, P30CA046592, 2P50CA127001, DK097153, CA16672, P30CA16672), the Sewell Family Chair in Genomic Medicine, the Cancer Prevention & Research Institute of Texas (CPRIT) (RP140672, RP150519, RP170067), the CPRIT Graduate Scholar Program, the American-Italian Cancer Foundation, MD Anderson’s Moon Shots Program®, the Broach Foundation for Brain Cancer Research, the Howard and Susan Elias Foundation, the Charles Woodson Clinical Research Fund and the University of Michigan Pediatric Brain Tumor Research Initiative.
The University of Texas MD
Anderson Cancer Center has united with fellow National
Cancer Institute (NCI)-Designated Cancer Centers and partner
organizations to issue a joint
statement urging the nation's physicians, parents and young adults
to get human
papillomavirus (HPV) vaccination back on track.
Decreased annual well visits and immunizations during the COVID-19 pandemic have caused a vaccination gap and lag in vital preventive services among U.S. children and adolescents – especially for the HPV vaccine.
Nearly 80 million Americans – 1 out of every 4 people – are infected with HPV, a virus that causes several types of cancers. Of those millions, more than 36,000 will be diagnosed with an HPV-related cancer this year. Despite those staggering figures and the availability of a vaccine to prevent HPV infections, HPV vaccination rates remain significantly lower than other recommended adolescent vaccines in the U.S. Even before the COVID-19 pandemic, HPV vaccination rates lagged far behind other vaccines and other countries’ HPV vaccination rates. According to 2019 data from the Centers for Disease Control and Prevention (CDC), slightly more than half of adolescents (54%) were up to date on the HPV vaccine.
Those numbers have declined further since the pandemic:
- Early in the pandemic, HPV vaccination rates among adolescents fell by 75%.
- Since March 2020, an estimated 1 million doses of HPV vaccine have been missed by adolescents with public insurance – a decline of 21% over pre-pandemic levels.
“MD Anderson has continued to emphasize the importance of cancer prevention throughout the pandemic and supports this joint effort to remind the public that HPV vaccination prevents multiple types of cancer,” said Ernest Hawk, M.D., vice president and division head of Cancer Prevention and Population Sciences. “Now is the time to re-prioritize HPV vaccination for adolescents, as we strive toward the achievable goal of protecting future generations from HPV-related cancers, including cervical and oropharyngeal cancers.”
The U.S. has recommended routine HPV vaccination for females since 2006 and for males since 2011. Current recommendations are for routine vaccination at ages 11 or 12 or starting at age 9. Catch-up HPV vaccination is recommended through age 26.
The CDC recently authorized COVID-19 vaccination for 12 to 15-year-old children, allowing for missed doses of routinely recommended vaccines, including HPV, to be administered at the same time. NCI-Designated Cancer Centers strongly encourage parents to vaccinate their adolescents and urge health care providers to use every opportunity to promote and complete vaccination.
“The HPV vaccine is one of our most important tools to prevent cancer,” said Maura Gillison, M.D., Ph.D., professor of Thoracic/Head & Neck Medical Oncology and co-leader of the HPV-Related Cancers Moon Shot®. “Most adults are exposed to HPV at some point in their lifetime and some will go on to develop cancer. HPV vaccination saves lives by ensuring adolescents are protected from future HPV-related cancers.”
More information about HPV is available from the CDC and National HPV Vaccination Roundtable. This is the third time that all NCI-Designated Cancer Centers have come together to issue a national call to action. All 71 cancer centers unanimously share the goal of sending a powerful message to parents, adolescents and health care providers about the importance of HPV vaccination for the elimination of HPV-related cancers.
Researchers at The University of Texas MD Anderson Cancer Center have developed a first-of-its-kind artificial intelligence (AI)-based tool that can accurately identify rare groups of biologically important cells from single-cell datasets, which often contain gene or protein expression data from thousands of cells. The research was published today in Nature Computational Science.
This computational tool, called SCMER (Single-Cell Manifold presERving feature selection), can help researchers sort through the noise of complex datasets to study cells that would likely not be identifiable otherwise.
SCMER may be used broadly for many applications in oncology and beyond, explained senior author Ken Chen, Ph.D., associate professor of Bioinformatics & Computational Biology, including the study of minimal residual disease, drug resistance and distinct populations of immune cells.
“Modern techniques can generate lots of data, but it has become harder to determine which genes or proteins actually are important in those contexts,” Chen said. “Small groups of cells can have important features that may play a role in drug resistance, for example, but those features may not be sufficient to distinguish them from more common cells. It’s become very important in analyzing single-cell datasets to be able to detect these rare cells and their unique molecular features.”
Developing methods to effectively study small or rare cell populations in cancer research is a direct response to one of the provocative questions posed by the National Cancer Institute (NCI) in 2020, designating this an important and underexplored research area. SCMER was designed to address the issue and to enable researchers to get the most out of increasingly complex datasets.
Rather than the traditional approach of sorting cells into clusters based on all data contained in a dataset, SCMER takes an unbiased look to detect the most meaningful distinguishing features that define unique groups of cells. This allows researchers not only to detect rare cell populations, but to generate a compact set of genes or proteins that can be used to detect those cells among many others. To highlight the utility of SCMER, the research team applied it to analyze several published single-cell datasets and found it compared favorably to currently available computational approaches.
In a reanalysis of more than 4,500 melanoma cells, SCMER was able to distinguish the cell types present using the expression of just 75 genes. The results also pointed to a number of genes involved in tumor development and drug resistance that were not identified as meaningful in the original study.
In a complex dataset of nearly 40,000 gastrointestinal immune cells, SCMER separated cells using only 250 distinct features. This analysis identified all the original cell types detected in the original study, but in many cases further defined subgroups of rare cells that were not previously identified.
Finally, the research team applied SCMER to study more than 1,400 lung cancer cells taken at various points in time after drug treatment. Using just 80 genes, the tool was able to accurately distinguish cells based on treatment responses and pointed to possible novel drivers of therapeutic resistance.
“Using state-of-the-art AI techniques, we have developed an efficient and user-friendly tool capable of uncovering new biological insights from rare cell populations,” Chen said. “SCMER offers researchers the ability to reduce highly dimensional, complex datasets into a compact set of actionable features with biological significance.”
The researchers have made SCMER freely available to the research community.
The research was supported in part by the Human Cell Atlas Seed Network from the Chan Zuckerberg Initiative Donor-Advised Fund, an advised fund of Silicon Valley Community Foundation (CZF2019-002432, CZF2019-02425); the Cancer Prevention & Research Institute of Texas (CPRIT) (RP180248, RP200520); and the National Cancer Institute (U01CA247760, U24CA211006, P30 CA016672).
In addition to Chen, co-authors from MD Anderson include Shaoheng Liang, a graduate student in Bioinformatics & Computational Biology at MD Anderson and Computer Science at Rice University, Houston, TX; Vakul Mohanty, Ph.D., and Jinzhuang Dou, Ph.D., both of Bioinformatics & Computational Biology; Qi Miao and Yuefan Huang, both graduate students in Bioinformatics & Computational Biology at MD Anderson and Biostatistics & Data Science at UTHealth, Houston, TX; and Muharrem Müftüoğlu, M.D., of Leukemia. Additional authors include Li Ding, Ph.D., Washington University of St. Louis, St. Louis, MO; and Weiyi Peng, M.D., Ph.D., University of Houston, Houston, TX. The authors declare no conflicts of interest.