Personalizing Cancer Medicine
Head and neck squamous cell carcinoma (HNSCC) is a biologically heterogeneous disease arising in the upper aerodigestive mucosa, spanning from the lips to the voice box. Classically, HNSCC is driven by habitual exposure to tobacco and alcohol. Recently, there has been an alarming rise in the number and proportion of HNSCC cases in the oropharynx (tonsil and base of tongue). This newly recognized epidemic results from oral infection with human papillomavirus (HPV), the same virus which causes cervical cancer. Standard treatments for HNSCC include surgery, radiation and cytotoxic chemotherapies. Cetuximab, an antibody against the epidermal growth factor receptor (EGFR), is the first and only FDA-approved molecularly targeted therapy for this malignancy. With standard treatments, HPV-associated HNSCC carries a favorable prognosis, whereas survival from HPV-negative cancers has improved only minimally even with intensification of conventional or targeted therapy. Unfortunately, no biomarker has been identified to date which predicts specific treatment response to approved drugs in HNSCC.
The major research focus of our Head and Neck Cancer Program (HNCP) is the identification of tumor or blood biomarkers which will help us implement “personalized” medicine for head and neck squamous cell carcinomas (HNSCC). Understanding genetic, signaling, and immune alterations in HNSCC will accomplish two goals:
- Development of new anti-cancer drugs for HNSCC, which target novel pathways; and
- Accurate identification of patients who will benefit from currently approved therapies.
Examples of emerging personalized therapy are abundant at UPMC Hillman Cancer Center. We routinely test HNSCC for the presence of HPV. Ongoing clinical trials are evaluating treatment de-intensification strategies for HPV-associated HNSCC, aiming to reduce long term toxicity while preserving excellent survival. We are implementing a panel of tumor biomarkers in patients with HNSCC, including genetic alterations (such as mutation) and aberrant protein expression implicated in HNSCC progression.
The long-term goal is to develop a robust personalized medicine approach by identifying individuals whose tumors harbor specific characteristics that can guide treatment selection. For example, selected p53 mutations are associated with inferior prognosis. Assessment of these mutations will inform enrollment in a clinical trial of post-operative treatment intensification. PIK3CA mutation or amplification has been shown to activate critical growth pathways in HNSCC and several other cancers. We are opening a clinical trial to test the efficacy of a PI3K pathway inhibitor in HNSCC patients. ERCC1 protein over-expression is implicated in resistance to cisplatin, the cornerstone chemotherapy in HNSCC. We will assess HNSCC tumors for ERCC1 expression, to allow us to deliver cisplatin to patients who are most likely to respond, and test alternative strategies in patients whose tumors appear resistant. In the laboratory, we have identified candidate protein and immune biomarkers of resistance to the EGFR inhibitor, cetuximab. As a direct result, we are developing multiple clinical trials to test new drugs hypothesized to overcome such resistance. Finally, we are studying an early imaging biomarker, the PET/CT scan, to rapidly identify patients unlikely to relapse after chemoradiation – ultimately to accelerate personalized drug development for HNSCC.
Overall, in the Head and Neck Cancer Program at UPMC Hillman Cancer Center, we are actively exploring how to integrate candidate biomarkers into our assessment and treatment of HNSCC to deliver on the promise of “personalized” cancer medicine.