PI3K/PTEN Targeted Therapy for HPV-associated Cancers

These data demonstrate that activating mutations in Pik3ca drive anal carcinogenesis together with HPV16 oncogenes, and that the PI3K/mTOR pathway is a relevant target for therapeutic intervention.

– (Shin et al. 2018, Clinical Cancer Research)

At a Glance

This research studied common genetic changes in a gene called PI3K, a type of mutation found frequently in HPV-associated anal, head, and neck cancers, with the goal of advancing knowledge to inform choices of anticancer drugs for HPV-associated cancers.

The researchers found that these genetic changes drove development of cancers in mice, but that drugs targeting PI3K did not necessarily inhibit human cancers, indicating a need to develop additional steps to assess whether a cancer will respond to a targeted drug therapy. A new type of culture system, called the tumor spheroid culture system, may provide that means.

The Challenge

The most common contributing factor in anal cancer is high-risk human papillomavirus (HPV), which is also implicated in a growing fraction of head and neck cancers. HPV is detected in 95 percent of human anal cancers, and anal cancer incidence and deaths have been increasing over the last decade. HPV type 16 is the genotype most commonly found. Mutations in the PI3K, encoded by the Pik3ca gene, are detected in approximately 20 percent of human anal cancers, meaning these mutations are an important target of research.

Project Goals

The goal of this project was to assess the role of activating mutations in PI3K, a signaling factor often mutated in human cancers and a major focus of targeted cancer therapies in human cancers caused by HPVs. The researchers assessed the importance of activating mutations in HPV-associated cancers in Aim 1, made use of human head and neck cancer (HNC) patient-derived xenografts (PDXs) to assess the response of these cancers to drugs that inhibit PI3K or downstream signaling pathways in Aim 2, and investigated in vitro tissue culture systems that might best allow doctors to predict response of HNCs to these drugs in Aim 3.

Results

Aim 1: The results provide clear evidence that mutations in PI3K associated with HPV drive the growth of anal, head, and neck cancer. The researchers and collaborators also demonstrated that allografts and 3D anal tumor spheroid cultures could be established from the mouse anal cancer model, and responded to a clinically relevant drug which is undergoing trials. This study is now published (Shin et al. 2018, Clinical Cancer Research), and will inform treatment options for patients with recurrent anal cancer.

Aim 2: This part of the study asked whether human HNCs with activating mutations in Pik3ca were responsive to targeted therapeutics that inhibit PI3K signaling. The results showed that the presence of activating mutations in Pik3ca did not predict response to the drugs targeting the PI3K signaling, either alone or in combination with the FDA approved drug Cetuximab.

Some PDXs were highly responsive to this combination of drugs, but their response did not correlate with the mutational status of the Pik3ca gene. These results add to a growing body of evidence suggesting that approaches that attempt to match biomarkers to optimal therapies in head and neck cancers remain complex and challenging. These studies were also published (Swick et al. 2017, Molecular Cancer Therapy).

Aim 3: This portion of the research focused on identifying culture methods for predicting response of HNCs to targeted drug therapies. A number of different culturing methods were attempted in experimental trials. The type of culturing technique used greatly influenced the responsiveness of the cells to the drug combination, with 3D tumor spheroid cultures being most resistant (Ayuso et al. 2019, Scientific Reports).

Lasting Impact

The results of the first study aim of this grant demonstrate that the TAK-228 inhibitor is highly effective in treating mouse anal tumors, suggesting that this or similar drugs, alone or in combination with other therapies, might help in the treatment of anal cancers in humans. The results of the second aim add to a growing body of evidence suggesting that approaches that attempt to match biomarkers to the optimal therapy remain complex and challenging, but that the potential benefits of targeted therapy in the majority of head and neck cancer patients who do not benefit from immunotherapy remain promising.