Martin McMahon, PhD
It’s not uncommon for cancer researchers to enlist the help of standard laboratory mice in their scientific endeavors. The mice used in the lab of Martin McMahon, Ph.D., however, are far from ordinary; they’re genetically designed miniature patients created to help unlock the secrets of cancer.
Building upon a previously identified method of cloning, McMahon has had incredible success generating mice that develop cancers that closely recapitulate the genetics and pathophysiology of the human disease. By understanding how cancer develops in a genetically tractable organism, he hopes to understand in greater detail the way that human cancers develop and respond to therapy.
McMahon begins with embryonic stem cells that are cultured in a petri dish into which DNA is inserted to incorporate very subtle and specific genetic mutations. Once cells with the correct properties are identified, they are reinserted back into a blastocyst from a mouse. That blastocyst is then injected back into a female mouse, where it will implant like a normal blastocyst and develop into a “chimeric” mouse pup, which is a mixture of the original embryo’s cells and the ES cells that were injected. When these chimeric mice are born, they can, in turn, be bred to generate mice for cancer studies. So far, McMahon’s lab has used such genetically manipulated mice to study four diseases: melanoma, lung, pancreatic, and thyroid cancer. Although they come from very different types of cells in the body, these cancers are all driven by the same mutations in genes whose biochemistry is understood in some detail.
Models offer insight across disease sites.
They are not, however, the only cancers that can be studied using McMahon’s mouse models. In fact, McMahon’s models have proven to be such a powerful tool that they’ve been given to many collaborators at UC San Francisco and to colleagues throughout the United States to investigate pediatric brain tumors, colon, prostate, and ovarian cancer, and many other non-cancer-related diseases.
“We try and build tools that have remarkable flexibility and allow us to do our own research,” says McMahon. “But we also give those tools, materials and mouse strains out to as many other research labs who want them so that they can be applied in clever ways by others.”
Besides allowing researchers to watch the progression of disease and better understand its link to cancer genetics, McMahon’s models also lend themselves to the development of new drugs—particularly pathway-targeted therapeutics. These treatments are personalized or specifically tailored to genetic abnormalities that occur in human or mouse-modeled cancers, and often have less toxic side effects than the standard treatments.
Immunotherapeutics is another area of growing interest that benefits from McMahon’s models. Rather than target cancer cells directly with often toxic side-effects, immunotherapies target the body’s own immune system to stimulate activity that can help fight off the cancer.
Cancer models, such as those designed by McMahon and his colleagues, open the door to studying how the immune system interacts with developing tumors because the tumors develop in mice that have fully functioning immune systems. Normally, a mouse’s immune system will recognize any transplanted human cells as being foreign and kill them. Because of this, the only way that human cells can be studied in a mouse is if the mouse doesn’t have a functioning immune system.
It is therefore impossible to study how immunomodulatory molecules work in this context. McMahon’s genetically engineered mouse models, however, have been created so that the mice spontaneously develop cancer on their own without the need to transplant foreign human cells. The intact mouse immune system is therefore free to interact with the developing tumor just as in the human setting, allowing scientists such as McMahon to study how molecules that modulate the immune system might influence tumor formation and growth in the mouse, and ultimately in humans.
As novel as the research of McMahon and the rest of the UCSF faculty already is, there are even more cutting-edge developments already in the works. Within the next few years, researchers at UCSF’s Helen Diller Family Comprehensive Cancer Center hope to sequence the genome of every patient who walks through its doors in order to gain knowledge specific to the patient and their tumor. This information will help define the mutations that are driving the tumor as well as assist the selection of the most effective and tailored method of treatment.
“Since all of my patients are furry and have four legs and a tail, I’m not qualified to give medical advice to people,” says McMahon. “But our clinics, our doctors, and our physicians are committed to using the most up-to-date science to inform patients about how they get their care. UCSF’s Helen Diller Family Comprehensive Cancer Center was designed as an institution committed to translational cancer research and state-of-the art cancer therapy so that our patients can take hope from the fact that they’re being treated with the most up-to-date, evidence-based medications.”
Dr. McMahon holds the Efim Guzik Distinguished Professorship in Cancer Biology, UCSF, and is also Director of Professional Education and Co-Leader of the Developmental Therapeutics Program, UCSF Helen Diller Family Comprehensive Cancer Center
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