Finding A Needle In A Haystack: How a Yale Study Used Genetic Implications to Treat Cervical Cancer

Sammi Pohly
By Sammi Pohly December 21, 2019 14:09

Finding A Needle In A Haystack: How a Yale Study Used Genetic Implications to Treat Cervical Cancer

Cancer is caused by a series of genetic mutations, and an understanding of these genetic mutations in cancerous cells is crucial to the future development of cancer treatment. Cervical cancer specifically, has a particularly poor prognosis, making mutation targeted treatment a significant “unmet medical need ,” an unofficial term often used to describe diseases with few 1 treatment options.

However, discovering what these mutations are and how they inhibit cellular function is like looking for a needle in a haystack. Dr. Alessandro Santin, the leader of Yale Cancer Center’s Gynecologic Oncology Disease Aligned Research Team, is helping pave the way towards making mutation-targeted cervical cancer therapies a reality. He and his team not only discovered mutations that led to the spread of cervical cancer, but also developed a treatment specific to these mutations.

Dr. Santin and his team performed whole-exome sequencing, a technique used to quickly sequence the protein-coding regions of the human genome, on the tumor cells of sixty-nine cervical carcinoma patients. They discovered mutations in a signaling pathway within cervical cancer cells.

“The signaling pathway is the method that the cell has to communicate what happens outside, to the inside of the cell,” explains Santin. These signaling pathways are usually controlled by a receptor on the surface of the cell which, once bound to an extracellular signaling protein, becomes activated and causes the subsequent activation of other proteins on the inside of the cell. These intracellular proteins are called “downstream” effectors, and the communication between these proteins and the rest of the cell controls cell function.

Dr. Santin and his team determined that 71% of all the tumor cells they sequenced contained at least one mutation in the genetic sequence ERBB2/PI3K/AKT/mTOR. Each of these genes codes for different proteins involved in an intracellular signaling pathway that controls apoptosis, controlled cell death, in cervical cancer cells. A mutation in the cell receptor coded for by the ERBB2 gene on the surface of cervical cancer cells resulted in the receptor being constantly activated. This persistent activation constantly signaled to the nucleus for the cell to divide, resulting in the uncontrolled proliferation of the cancerous cells and the prevention
of cell death.

The group then went on to identify a treatment that targeted the ERBB2 and P13K mutations in cell cultures and in mice. P13K codes for the downstream effector protein, PIK3CA. A combination of already existing cancer drugs, copanlisib (approved to treat
lymphoma) and neratinib (approved to treat breast cancer), proved to be particularly effective at stopping cell growth and proliferation. The neratinib blocked the mutated receptor on the surface of the cell, causing it to deactivate, while the copanlisib inactivated the PIK3CA protein. Dr. Santin says that targetting both the receptor and a downstream signaling protein makes it “much more difficult for the cell to develop resistance” against the treatment.

Santin believes that the second part of his study, the discovery of the effectiveness of the copansilib and neuratinib combination therapy, is the most important. While other studies have looked to the “genetic landscape” of cervical cancer, none had been able to identify whether the discovered mutations were important or not. “They only speculate that this mutation may be important. Here, instead, we have demonstrated that [it is important]. This preclinical part is
crucial, because otherwise you never know if a specific mutation may be a trigger.”

The copanslib and neuratinib combination therapy has tremendous prospects, and will shortly move into clinical trials.

Sammi Pohly
By Sammi Pohly December 21, 2019 14:09
Write a comment

No Comments

No Comments Yet!

No comments yet.

Write a comment
View comments

Write a comment

Your e-mail address will not be published.
Required fields are marked*