With therapies lagging behind the surge in cases of human papilloma virus-related oropharyngeal squamous cell carcinomas surging, surgeon and scientist Devraj Basu, MD, PhD, FACS, last summer 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 at the University of Pennsylvania, 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 overarching goal 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 the 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+ OPSCC 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.
The standard multimodality therapies for HPV+ OPSCC are generally effective for the majority of patients but have acute toxicities as well as lasting effects that leave permanent treatment-related disabilities in many survivors. This toxicity is spurring efforts to de-escalate therapy—while maintaining high cure rates—by using minimally invasive surgery, limiting radiation doses and fields, and/or avoiding cytotoxic chemotherapy.
However, Dr. Basu says, the current protocol for determining which patients should have their therapy de-escalated “mostly relies on clinical and pathologic features that have limited prognostic and predictive accuracy, and molecular biomarkers of therapy response and recurrence risk remain inadequate for standard clinical application.”
A “sizable minority” of HPV+ OPSCC recur after standard therapy, according to Dr. Basu, 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 reductions in toxic treatment for patients who are the most easily cured.
A head and neck surgeon and a cancer biologist, Dr. Basu is focused on leveraging a molecular understanding of HPV-mediated oncogenic mechanisms to develop predictive biomarkers and novel preclinical therapeutic approaches that 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 are 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 are 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.
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 which 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 exploring the interface of HPV+ OPSCC with the immune system and working to activate anti-tumor immunity by targeting mechanisms of DNA repair in the tumor. And Jianxin You, PhD, a tumor virologist, is developing a new lipid nanoparticle-based strategy to reverse STING pathway suppression by HPV, which limits 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.”
A more complete understanding
Nearly 20 years ago, Gregory S. Weinstein, MD, FACS, and Bert W. O’Malley Jr., MD, developed transoral robotic surgery (TORS) for T1/T2 OPSCC. Its FDA approval changed the therapeutic landscape. However, most HPV+ OPSCC patients who undergo TORS at Penn still need adjuvant radiation, and about 25 percent also require chemotherapy. Moreover, surgery is currently not deemed appropriate for up to half the HPV+ OPSCC patients seen at Penn.
Dr. Basu aspires to modernize all aspects of care for this disease in the same way that TORS once did for the surgical treatment. He’s doing so by striving to understand the biology of these tumors and leveraging the extensive cancer biology expertise that surrounds him at Penn to develop a more precise path to less treatment toxicity and greater therapeutic efficacy.