Big Things, Small Beginnings
Jefferson surgeons are exploring new therapies that may make standard cancer treatments even more effective
Adam Luginbuhl, MD; David Cognetti, MD, co-director, Jefferson Center for Head and Neck Surgery; William Keane, MD, chair, Department of Otolayryngology – Head and Neck Surgery and co-director, Jefferson Center for Head and Neck Surgery; and Joseph Curry, MD
By Zach Nichols
In Haiti, up-to-date oncology care is far from commonplace. Routine cancer treatments such as radiation therapy are completely unavailable. CHANCE (Complex Head and Neck Care and Education), Jefferson’s surgical mission to the island nation, is changing that, bringing skilled surgical techniques and advanced training to the clinics that serve the local population.
But Joseph Curry, MD Res ’09, David Cognetti, MD Res ’07, and Adam Luginbuhl, MD Res ’12, are also hard at work back home, imagining the next generation of head and neck cancer treatments. Through the newly formed
Squamous Cell Carcinoma Tumor Ecology and Microenvironment (STEM) research group, they are striking at the roots of a growing cancer epidemic in the United States. Squamous cell carcinoma (SCC) typically affects the outer layers of epithelial cells and is generally thought of as skin cancer, though it also arises in the lining of other organs and can occur in the mouth, throat, esophagus, lungs, cervix, and other areas of the body.
Because of SCC’s pervasiveness, STEM’s work has implications that span the whole body, making STEM a multidisciplinary collaboration among Jefferson’s departments of Head and Neck Surgery, Dermatology and Cutaneous Biology, Cancer Biology and Immunology, Pathology, Thoracic Surgery, Radiation, and Medical Oncology.
New Kind of Patient, New Kind of Challenge
Some types of SCC are caused by the human papillomavirus (HPV), specifically cervical and oropharyngeal (throat) cancers. While cervical cancer is still the leading cause of cancer-related death in the developing world—especially in countries like Haiti—it has steadily decreased due to screening. However, oropharyngeal cancer has reached epidemic status in the United States and worldwide. While only a very small fraction of those exposed to HPV develop cancer, the trend is alarming given that the CDC recently estimated that 85 percent of adult Americans have been exposed to the virus.
“HPV vaccination is great, and its benefits to both men and women are huge,” says Cognetti, “But the carcinoma that HPV causes, especially in the head and neck region, is one of the only kinds of cancers that is still increasing.”
With a 20-year latency period from exposure to onset, some experts have attributed the current rise in HPV-related SCC in part to more permissive sexual attitudes that arose in the ’60s and ’70s. Though researchers expect rates to stabilize with increased awareness and immunization, clinicians are starting to see new kinds of patients coming into their offices and ORs.
The typical profile of a patient with a head and neck malignancy is a 65-year-old man who has smoked most of his life. But now Curry, Cognetti, and Luginbuhl are treating patients in their 30s who have been infected by HPV and developed SCC.
“While oropharyngeal cancer was only about 15 percent of head and neck cancers 20 years ago, it now represents 1 in 3 of the new head and neck cancers seen at Jefferson,” Curry says.
The five-year survival rate for the former cohort is not great; age and comorbidities from lifestyle often mean that their bodies are not always able to handle the side effects of treatment. However, among the younger patients, who are being cured at a rate of 90 percent, life expectancy is often projected for decades after treatment. But with this good news comes new challenges.
“The area we’re typically operating on is densely packed with all kinds of essential anatomy: eyes, nerves, and the carotid arteries, as well as the really complicated muscles involved in speech and swallowing,” says Cognetti. “If we do a radical resection, then a 38-year-old with HPV-caused carcinoma is going to be living with the side effects for a long time.”
This is the idea behind robotic surgery, which enables Cognetti and company to work precisely in tight spaces, minimizing impact on areas surrounding a tumor. It is also where STEM really stands out, as the prime mover on a number of clinical-pharmaceutical research initiatives that are promising to revolutionize head and neck cancer care.
Old Drugs, New Tricks
As STEM’s name suggests, a cancer tumor and its relationship to the body can be thought of as an ecology and a microenvironment—as something both expansive and self-contained. These interconnected ways of thinking inform two novel approaches that Curry, Cognetti, Luginbuhl, and their team of surgeons, oncologists, and scientists are taking to attack SCC.
The first is the immunotherapy angle, which has been a hot topic in the world of oncology. The idea behind it is simple: Our body has an innate ability to protect itself from pathogens—why not use the “home team advantage?” The implementation is another story. “The immune system is a kind of finely tuned organ,” says Luginbuhl. “A large part of how it functions involves chemically communicating information about how the body’s doing.” Cell signaling is integral to tumor resilience, as cancerous cells shroud themselves in proteins that tell the immune system that it’s OK not to attack.
What’s more, tumors use these signaling pathways to communicate with the host, “asking” for nutrients and other growth-promoting factors. “The tumors we see with the greatest inflammatory response are actually doing the worst,” Luginbuhl says. “It just feeds the cancer and maintains an otherwise permissive immune environment.”
But STEM is working to change this through a unique combination of the drugs tadalafil and nivolumab. Aside from its marketed purpose as a male potency aid under the brand name Cialis, tadalafil has been shown to increase the number of cells capable of killing cancer. Nivolumab, on the other hand, has been shown to help instigate an immune attack on the malignant intruders.
In theory, these two independently tested pharmaceuticals will have a synergistic effect and create a stronger immune response. A chemical one-two punch, tadalafil primes the immune system and nivolumab follows up, taking the brakes off of the immune cells. The treatment is currently being tested in a clinical trial funded by Bristol-Myers Squibb.
In another industry-sponsored trial, the STEM team is taking a different tack to fighting SCC: disrupt the internal workings of the tumor’s cellular ecosystem. Though we sometimes think about a tumor as a monolithic mass— cancer and noncancer—the kinds and functions of cells within the tumor often vary significantly. The cancer cells interact with normal cells and change the way they behave; the tumor, in a way, hijacks or subjugates normal cells and systems to benefit cancer growth.
The team has tested metformin, a very common and safe drug used to treat diabetes, which has been shown in the lab to “starve” and consequently kill cancer cells by inhibiting their ability to perform efficient metabolism. Preliminary data have shown that the drug contributes to a reduction in tumor size in animals, an exciting proof of concept. Based on that work, the group went on to perform a clinical trial in head and neck cancer patients.
“Patients were very excited at the notion of using a safe drug to learn about new ways to fight cancer, so we were able to fill that trial in about 18 months. We enrolled 50 patients on treatment with standard diabetic doses of metformin,” Curry says. “What we found is that metformin resulted in increased rates of death of tumor cells, and it also seemed to free some of the noncancer cells of the tumor from the effects and control of the cancer.”
This was the first trial of its kind in head and neck cancer, and it may open the door to mechanisms for targeted therapies against cancer. Now STEM is looking to dial in the dosages and combine other therapies to optimize the effects of the drug and to investigate evidence that suggests metformin may also protect healthy cells against the effects of radiation treatments.
“We don’t think metformin alone is likely to knock out cancer, but we do think that it could be the jab that sets up the right hook,” Curry says.
More Options, Minimal Impact
In the age of personalized medicine, the cutting edge of oncology is not a magic bullet that will once and for all cure cancer. Rather, it’s about a greater repertoire of strategies that can target the specific malignancies afflicting individual patients.
The experimental pharmaceuticals STEM is investigating, together with familiar treatment options such as surgery, chemo, and radiation, could offer a low-impact way of damaging a cancer tumor at a fundamental level, severing its parasitic relationship with a patient’s immune system and disrupting the most dangerous cells’ ability to feed themselves. The attendant decrease in tumor size will improve the effectiveness of now-standard interventions and the precision with which surgeons like Curry, Cognetti, and Luginbuhl can operate.
Whether it’s a younger patient suffering from HPV-caused SCC with their whole life ahead of them or a frail, older patient who can’t take the full-court press of treatment, these new therapies promise to make procedures, dosages, and side effects smaller and the chance of a happy ending bigger.