New Molecular and Gene Targets for Cervical Cancer Therapy Identified

A research team in the The Cancer Genome Atlas (TCGA) Research Network has found novel molecular characteristics as well as genomic features of cervical cancer which can be used for classification of the cancer. Such sub-classification will aid in developing targeted therapies which could be more effective for the patient. The study, published in Nature, was a comprehensive analysis of genomes conducted on 178 primary cervical cancers and found that

• More than 70 % of the tumors had alterations in the genes.
• One or both of the two important cell signaling pathways were affected.
• A subset of tumors did not exhibit any sign of an infection by the human papillomavirus (HPV) infection.

This was a multilaboratory study with the involvement of scientists from National Human Genome Research Institute (NHGRI), The National Cancer Institute (NCI) and the National Institutes of Health (NIH).

Cervical Cancer

Cervical cancer is a cancer of the cervix, which is the narrow opening from the vagina into the uterus. The normal color of the cervix is a pink color, covered with squamous cells that are flat and thin. The cervical canal is made up of columnar cells while the area where these cells meet is called the transformation zone or the T-zone. The T- zone is the most common location for a cancer of the cervix.

• 80 to 90% are squamous cell cancers
• 10 to 20% are adenocarcinomas
• In the U.S, over 12,000 women are diagnosed with cervical cancer each year
• 4,000 of women die every year due to cervical cancer
• Worldwide, 500,000 new cases of cervical cancer are detected every year
• 250,000 deaths occur each year worldwide due to this cancer
• Pap smear test is used to detect cervical abnormalities early

The cancer most often affects women who are middle aged, between 35-55 years of age; it seldom occurs in women younger than 20 years of age.

The Acting Director of The National Cancer Institute, Dr. Douglas Lowy, said that the vast majority of cervical cancer incidences are due to persistent infection with HPV that are oncogenic. There are effective vaccines which offer a means of prevention against some of the most oncogenic types of HPV. However, the only hitch to the vaccination program, according to the director, is that most women who will develop this cancer over the next 2 years are beyond the age of protection by the vaccine. Therefore, there is still an urgent need to identify therapies that will prevent the development of this type of cancer. This latest TCGA analysis is expected to improve efforts to identify drugs which target important cervical cancer genomes along with the HPV genes.

Similarity with Endometrial Cancer

A significant finding in this study was that there were 8 cervical cancers which showed molecular similarity with endometrial cancer. These were characterized by

• Increased frequency of mutation in KRAS, PTEN and ARID1A genes
• Being mostly HPV-negative

Dr. Jean-Claude Zenklusen, Director of the TCGA program office said that the presence of endometrial like cervical cancers that were HPV negative showed that not all cervical cancers were associated with an HPV infection. It showed that a small percentage of these tumors could be solely associated with genetic or other factors. The Director of the program, Dr. Jean, further stated that this was one of the most important aspects of the TCGA program.

Immunotherapies

The research team tried to identify genes that were over expressed in order to predict the response to immunotherapies. They found that the following genes were amplified:

• CD274 that codes for the PD-L1 immune checkpoint protein
• PDCD1LG2 that codes for the PD-L2 immune checkpoint protein

There are several previous immunotherapeutic agents that have been found to be effective against checkpoint inhibitors.

Novel mutations that were identified during the study include

• MED1
• CASP8
• ERBB3
• TGFBR2
• HLA-A

Potential Therapeutic Target

During the study, there were several instances of cervical cancer where the BCAR4 genes were fused and resulted in a non-coding long RNA that was found to be responsive to lapatinib. This is a drug taken orally by breast cancer patients as it inhibits an important pathway. This could be a potential drug therapy for cervical cancer patients with this mutation.

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Signaling Pathways

The study findings also revealed that nearly three fourths of the cervical cancer cases were due to genetic alterations in either one or both the following pathways

• PI3K/MAPK
• TGF-beta

The study provided many significant targets for cervical cancer therapy but the scientists involved in the study were not able to determine if HPV positive cervical cancer would respond to therapy similar to HPV negative cervical cancer. A previous study showed that the presence of HPV antibodies in people with certain cancers was a marker of better prognosis. The new targets for therapy identified by this study could, hopefully, aid in improving the prognosis of patients without HPV antibodies too.

References:

1. Cervical Cancer Overview - (http://www.nccc-online.org/hpvcervical-cancer/cervical-cancer-overview/)

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Source-Medindia