For decades, the SRC enzyme has been a well-known player in cancer biology, notorious for its role in promoting tumor growth. Traditionally believed to reside exclusively inside cells, SRC has now been discovered on the surface of tumor cells, offering a new target for cancer therapies. Researchers at the University of California, San Francisco (UCSF) have identified this unexpected presence, potentially revolutionizing treatment for various cancers, including bladder, colorectal, breast, and pancreatic.
This groundbreaking discovery was made as scientists observed that cancer cells, in their rapid division, produce excessive waste. While healthy cells manage to break down and recycle this waste, tumor cells often fail, leading to the expulsion of cellular debris. This process inadvertently displays the SRC enzyme on the cell surface, making it accessible to antibody-based therapies.
New Horizons in Cancer Treatment
By targeting the surface-exposed SRC enzyme with antibodies carrying radioactive materials or those that recruit immune cells, researchers successfully killed cancer cells and reduced tumor sizes in mice. This approach could potentially be applicable to half of all tumors, marking a significant advancement in cancer treatment.
“No one thought to look for it on the outside,” said Jim Wells, PhD, professor of Pharmaceutical Chemistry at UCSF and senior author of the study published in Science on March 12. “Our discovery enables us to test proven immunotherapies on this new tumor target.”
The Journey of SRC to the Cell Surface
The SRC gene, identified in the 1970s by UCSF’s J. Michael Bishop, MD, and Harold Varmus, MD, was the first oncogene discovered, earning them a Nobel Prize in 1989. Since then, efforts to inhibit SRC with drugs targeting the enzyme inside cells have been largely unsuccessful, as these therapies also impact healthy cells.
To understand how SRC reaches the cell surface, scientists tracked its movement in cancer cells grown in laboratory conditions. They found that the enzyme was swept up in the cell’s overwhelmed disposal system. Normally, cells encapsulate waste in small sacs for breakdown and reuse. However, in cancer cells, these sacs fuse with the cell membrane, expelling their contents and exposing SRC externally.
“We saw that SRC was getting swept out onto the outer membrane, where it sat exposed like a red flag,” explained Corleone Delaveris, PhD, the study’s first author, who conducted the research as a post-doctoral fellow in Wells’ lab and now works at Inversion Therapeutics.
Implications for Future Therapies
The presence of SRC on the surface of tumor cells, but not on healthy tissue or immune cells, suggests a high specificity for targeting cancer with antibody therapies. In collaboration with UCSF professor of Radiology Michael Evans, PhD, the research team directed experimental radioactive antibodies at SRC in mice implanted with human tumor cells, confirming their accumulation in cancerous tissues. Additionally, they engineered antibodies to enhance immune cell recognition and destruction of cancer cells.
UCSF has licensed these antibodies and related molecules to Inversion Therapeutics to explore their therapeutic potential further. “We went all the way from the discovery to developing two preclinical therapies that target SRC – and they worked,” Wells stated. “It’s truly exciting.”
Support and Future Directions
This research was supported by several institutions, including the National Institutes of Health and the UC Cancer Research Coordinating Committee. The study’s authors, including Rita P. Loudermilk, Apurva Pandey, PhD, and others, have laid the groundwork for potential clinical applications of this discovery.
With the licensing of these innovations to Inversion Therapeutics, the path is set for further development and possible clinical trials. The implications of this discovery extend beyond immediate therapeutic applications, offering new insights into cancer biology and the potential for more targeted, effective treatments.
As the scientific community continues to explore the therapeutic potential of targeting surface-exposed SRC enzymes, the hope is that this approach will lead to more effective, less harmful cancer treatments, ultimately improving patient outcomes and survival rates.
