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READ MOREPublished on August 6, 2019 in Research
An enzyme that serves as a link between oncogenes and the lipids that make-up cells’ membranes may be an important new drug target to treat glioblastoma and other tumors
Glioblastoma, like all cancers, develops and progresses as cells begin to multiply and grow out of control, forming a tumor.
Mutations to a protein known as EGFR are one of the drivers of this unchecked cell growth. The EGFR protein is actually what is known as a receptor, as it acts like a molecular antenna of sorts, receiving signals from outside the cell and transmitting them to the machinery inside the cell. When EGFR is mutated in glioblastoma tumors, it continuously sends survival signals into the cell, providing the instructions for constant and aggressive growth. This is known as “oncogenic signaling.”
As researchers with NBTS’ Defeat GBM Research Collaborative (Defeat GBM) and others have previously discovered, the most common type of EGFR mutation found in glioblastoma (known as EGFRvIII) can also cause a major shake-up to how cells consume and utilize nutrients in order to provide the fuel they need to sustain their progression. This is known as “metabolic reprogramming,” as the cancer cell’s metabolism is uniquely altered.
The relationships between genomic-driven mutations like EGFRvIII and cellular behavior, however, are not fully understood.
In a paper recently published in the leading scientific publication, Cell Metabolism, a team of Defeat GBM researchers led by Dr. Paul Mischel of UC San Diego and Ludwig Cancer Research have discovered a new piece of the puzzle — a potential missing link between how oncogenic signaling and metabolic reprogramming conspire to drive tumor glioblastoma growth.
Advances in DNA sequencing technologies have reshaped our understanding of the molecular basis of cancer, suggesting a new and more effective way of treating cancer patients. However, to date, precision oncology has yet to benefit many patients, motivating a deeper search into understanding how genetic alterations in tumors change the way cancer cells behave, and potentially unlocking new ways to more effectively treat patients.
Attribution: Dr. Mischel
What Dr. Mischel and his collaborators — including other Defeat GBM leaders, Drs. Frank Furnari, Webster Cavenee, and Tim Cloughesy — found is that oncogenic signaling induced by the EGFRvIII mutation changes the composition of cells’ membranes (also called a plasma membrane), which separates the interior of cells from the outside environment and are made of molecules called lipids. They also found that this change to the structure of the plasma membrane, in turn, helps maintain the EGFR-driven oncogenic signaling, since this receptor resides within the membrane (and needs to stay there to function).
To see if this process could be exploited to treat patients with glioblastoma, the researchers searched for the event that triggers these structural changes. Doing so, they identified an enzyme in cells called LPCAT1. LPCAT1 was found to be overactive in glioblastoma tumors with the EGFRvIII mutation, and plays a unique role in building the components of a cell’s plasma membrane. However, when LPCAT1 gets forced into action from EGFRvIII signaling it increases the saturation of a certain type of lipid (called a phospholipid) within the composition of the membrane. The altered plasma membranes with the extra phospholipids become inviting hosts for receptors, like the mutated EGFRvIII, that transmit growth signals to cells. Thus, a self-sustaining process emerges whereby EGFRvIII both generates, and benefits from, LPACT1’s activity in reshaping the structure and composition of the tumor cells’ plasma membranes.
“LPCAT1 links altered cancer genomes with [abnormal] metabolism and plasma membrane remodeling to drive tumor growth through the production of saturated [phospholipids],” Dr. Mischel and his co-authors wrote in the recent paper. “These results highlight LPCAT1 as a critical node integrating genetically altered [EGFR] signaling with lipid remodeling to alter the physical properties of the plasma membrane and create a pro-tumor cellular state.”
Tumors become dependant on this altered membrane structure for continued EGFRvIII oncogenic signaling, and thus LPCAT1 becomes crucial for glioblastoma to maintain its relentless progression.
Importantly, Dr. Mischel and his team found that targeting and knocking-out LPCAT1 halted tumor growth and significantly extended the survival in laboratory models of glioblastoma. In fact, targeting this enzyme caused the EGFR receptors to move out of the plasma membrane, disrupting their ability to send survival/growth signals and causing “massive tumor cell death.” These results indicate that LPCAT1 can be considered a “very compelling new drug target.”
Dr. Mischel and his co-authors say that future studies will aim to better understand how oncogenic signaling controls LPCAT1 levels and how specific phospholipids regulate the activity of mutated receptors like EGFRvIII. Finally, additional work is needed to identify, develop, and evaluate new potential drugs that effectively target LPCAT1 in GBM patients.
“[Defeat GBM] gave us the opportunity to work differently, to ask difficult, big and important questions,” Dr. Mischel said. “It catalyzed a body of work that has been published at the highest levels of science and has led to the identification of new targetable mechanisms in GBM, coupled with compounds that have promise for clinical development and testing in patients.”
TAGGED WITH: brain cancer, brain tumor, Cancer, GBM, glioblastoma, high-grade glioma, Treatment, precision medicine, glioma, Defeat GBM