New Penn Center aims to better understand—and improve outcomes for—HPV-related oropharyngeal cancers
With cases of human papilloma virus-related oropharyngeal squamous cell carcinomas surging and therapies lagging, Devraj Basu, MD, PhD, FACS, is determined to accelerate the identification of key biomarkers and develop personalized therapeutic strategies.
In 2024, surgeon and scientist Devraj Basu, MD, PhD, FACS established the HPV+ Head and Neck Cancer Translational Center of Excellence at the Abramson Cancer Center.
The center’s overarching goals, according to Dr. Basu, an Associate Professor of Otorhinolaryngology—Head and Neck Surgery at the Perelman School of Medicine, are to accelerate the identification and clinical application of biomarkers that distinguish HPV+ head and neck cancer patients at high-risk of tumor recurrence and to develop personalized therapeutic strategies that exploit the biologic differences among HPV+ head and neck cancers.
Personalized medicine is regarded as the objective of modern cancer care. While significant strides have been made in risk stratification to personalize treatment of breast, colon, and prostate cancers as well as many other solid tumors, the same cannot be said of head and neck cancers, particularly HPV-related oropharyngeal squamous cell carcinomas (HPV+ OPSCC).
“There is limited personalization,” Dr. Basu says. “The standard clinical tools that distinguish high risk from low risk have improved somewhat, but they still perform relatively poorly. Therefore, we need tools that tell the high-risk people from the low-risk people so that we can treat the high-risk people with novel treatments that may target their more aggressive biology and continue to de-escalate the standard treatments that are moderately effective at controlling cancer in the low-risk people, while looking for treatments that are tailored to their distinct biology that don’t come with much toxicity.”
The standard of care has major acute and late toxicities
HPV+ OPSCCs are rising in incidence in the United States, where they have surpassed cervical cancer as the most common HPV-related malignancy. Despite the availability of HPV vaccination, HPV+ OPSCC will likely become the most common head and neck cancer type in the United States by 2030.
For most patients, the standard therapies for HPV+ OPSCC are effective. However, these multimodality approaches have acute toxicities for the majority of patients and can leave permanent treatment-related disabilities. This toxicity is spurring efforts to reduce therapy intensity—while maintaining high cure rates—through the use of minimally invasive surgery, limiting radiation doses and fields, and/or avoiding cytotoxic chemotherapy.
Dr. Basu explains that the current protocol for deciding which patients should have de-escalation therapy relies primarily upon clinical and pathological features that have limited prognostic and predictive accuracy. Moreover, the molecular biomarkers of therapy response and recurrence risk remain inadequate for standard clinical use.
According to Dr. Basu, a “sizable minority” of HPV+ OPSCC recur after standard therapy, and the mechanisms and markers of therapy resistance that distinguish these tumors from their more treatment-sensitive counterparts remain poorly defined. This recurrence risk prevents significant de-escalation of toxic therapy for patients who are among the most easily cured.
A head and neck surgeon and a cancer biologist, Dr. Basu’s research is focused on leveraging a molecular understanding of HPV-mediated oncogenic mechanisms to develop predictive biomarkers, that with novel preclinical therapeutic approaches, can be advanced into clinical trials.
Exploration and experimentation
To achieve these goals, he’s organized the center’s operations around three main categories: basic science research, translational research focused on pre-clinical therapeutics, and clinical trial development.
On the basic science front, “We’re evaluating a handful of mechanisms, mostly related to how these tumors resist radiation and chemotherapy, and particularly the way that mitochondria mitigate the oxidative stress of standard treatment,” Dr. Basu says. “Those are treatments that kill through oxidative stress in some tumors. The oxidative stress kills through damaging all macromolecular constituents of cells—proteins, lipids, but also, in large part, DNA. We’re very interested in how different versions of this cancer, different tumors, signal their DNA repair machinery in maintaining the integrity of their genomes.”
The center’s early translational research has focused on comparing the large patient populations who responded well to the standard multimodality therapies for HPV+ OPSCC to the small populations who did not, using sophisticated matching of other patient characteristics, says Dr. Basu, who expects a paper detailing this exploration to be accepted for publication in the coming months.
“We’re evaluating a handful of mechanisms, mostly related to how these tumors resist radiation and chemotherapy, and particularly the way that mitochondria mitigate the oxidative stress of standard treatment,” Dr. Basu says.
A DNA damage response expert in the Department of Cancer Biology, Eric Brown, PhD, is working to characterize the DNA repair defects in this disease so that they can be tested in a preclinical therapeutic trial design. He is a founder of a company, incubated at the University of Pennsylvania, that’s generated new compounds that target the signaling within DNA damage response pathways. Dr. Basu says two of these therapeutics are being studied in preclinical models at the Center, with and without radiation.
Meanwhile, another cancer biologist, Ahmed Diab, PhD, is researching the interface of the immune system with HPV+ OPSCC, and working to target mechanisms of DNA repair in tumors to activate anti-tumor immunity. Jianxin You, PhD, a tumor virologist, is developing a lipid nanoparticle-based strategy to reverse STING pathway suppression by HPV, which restrains the immune system’s ability to detect this type of cancer.
With the help of medical oncologists Roger Cohen, MD and Lova Sun, MD, MSCE and radiation oncologist J. Nicholas Lukens, MD, Dr. Basu anticipates the center will launch multiple clinical trials within the next year, including one in which a random selection of participants will be treated with one of the low-toxicity therapeutics from Dr. Brown’s company in combination with, Dr. Basu says, “a very low-dose and limited field of radiation, with the expectation that, for these low-risk patients, doing so will cause them minimal problems and will induce responses that are deep enough that one can then perform surgery and not need to add a great deal of additional treatment, perhaps no treatment, thus allowing us to de-escalate the toxicity of what is, in at least surgically treated patients, radiation for most and chemotherapy for some.”
TORS and a more complete understanding
Approximately 20 years ago, Gregory S. Weinstein, MD, FACS and Bert W. O’Malley Jr., MD of Penn ENT developed transoral robotic surgery (TORS) for T1/T2 OPSCC. The subsequent FDA approval for TORS changed the therapeutic landscape worldwide for head and neck cancers. Despite the efficacy of TORS, most HPV+ OPSCC patients who have the procedure at Penn will need adjuvant radiation, and ~25% require chemotherapy. Moreover, surgery is currently not deemed appropriate for up to half the HPV+ OPSCC patients seen at Penn.
Dr. Basu aims to modernize all aspects of care for this disease, just as TORS revolutionized surgical treatment. He’s doing so by striving to understand the biology of these tumors and leveraging the extensive cancer biology expertise surrounding him at Penn to develop a more precise path to less treatment toxicity and greater therapeutic efficacy.