Chromosomal instability as a mechanism of radiation sensitivity

Chromosomal Instability (CIN) is an ongoing rate of chromosome missegregation events over the course of multiple cell divisions, and is common in human tumors.

Our laboratory and others have shown that combining two independent insults that each cause tolerable levels of CIN results in high CIN, which leads to cell death and tumor suppression due to loss of essential chromosomes. Ionizing radiation can induce CIN; thus we hypothesize that higher levels of pre-existing CIN in tumors sensitizes cancer cells to radiation therapy.

We also study how different chemotherapeutics affect CIN and if this could be a novel mechanism of radiosensitization. For example, taxanes have long been thought to increase radiation sensitivity by inducing mitotic arrest. Docetaxel is a taxane used to treat many cancers, including head and neck cancer. We found that when it is used at clinically relevant concentrations, there is no mitotic arrest, and instead, it induces multipolar spindles which leads to cell division in 3 or more directions and cell death. Thus, we discovered a novel mechanism by which docetaxel induces cell death and sensitizes cells to radiation.

Human Papillomavirus and Chromosomal Instability

Human Papilloma Virus (HPV) is recognized as a significant cause of head and neck cancer and represents a unique clinical entity. Many HPV+ head and neck cancers are more sensitive to radiation then HPV- cancers yet we currently do not have a biomarker to inform us which patients will be cured with a lower dose of radiation, and which patients may need escalated treatment. This is a big issue in radiation oncology because many clinical trials are trying to treat everyone with HPV+ tumors with a lower dose, but we are learning that 10-15% of these patients will have residual or recurrent disease after receiving the lower dose, and hence a poor prognosis. This is a clear example of “one size does not fit all” and it is imperative that we think about the biology of each patient’s tumor to determine the most effective treatment.

Another main interest of my lab is therefore to study how different HPV genotypes (i.e. HPV16 v. HPV18) and different HPV viral genes (i.e. E2, E5, E6, E7) affect CIN. We recently reported that HPV+ head and neck cancers had significantly more misaligned chromosomes than HPV- cancers (A). We found that the HPV oncoprotein E6 causes polar chromosomes (Panels G,H) by causing the specific degradation of the mitotic kinesin CENP-E (panel I). Further work will determine if this has implications for treatment response.

Determine how HPV and CIN affect innate immunity in the context of radiotherapy

Many cell types sense exogenous DNA through the cytosolic DNA receptor GMP-AMP synthase (cGAS), which produces a second messenger cGAMP which activates STING, and ultimately results in a type I interferon immune response. Cells utilize this pathway to protect the host from viral and bacterial infection as well as from genomic instability, which can also cause cytosolic DNA. Many cancer cells have lost the cGAS/STING pathway to avoid immune detection and aid in their survival. I am interested in determining if cancers caused by Human Papilloma Virus (HPV) have differential activation of the cGAS/STING pathway at baseline and in response to radiation compared to HPV negative cancers, and whether this affects the immune response to the tumor. Immunotherapy has revolutionized cancer treatment, but it has not shown robust activity in head and neck or cervical cancer to date. More research is sorely needed to determine the most effective combinations of drugs and radiation. We will be studying how the unique biology of each tumor, such as HPV gene expression and CIN, affects anti-tumoral immunity.