Comprehensive cancer study assesses potential targets for personalized medicine and finds new ones

May 18, 2017, Baylor College of Medicine
Dr. Chad Creighton. Credit: Baylor College of Medicine

Looking to improve cancer treatment, a multi-institutional research team has taken a comprehensive approach to evaluating which molecular changes in cancer cells are most likely involved in the development of the disease. This approach resulted in the confirmation of previously known cancer molecular changes and in the discovery of others that had not been typically linked to cancer before. Targeting particular patient alterations with specific drugs might help one day improve response to treatment. The report appears in Cancer Cell.

"We studied the PI3K , one of the most important pathways of the cell," said senior author Dr. Chad Creighton, associate professor of medicine and member of the Dan L Duncan Comprehensive Cancer Center Division of Biostatistics at Baylor College of Medicine. "A is a chain of events involving several proteins. The PI3K pathway has a number of diverse functions, including altering the cell's metabolism and driving cell growth and proliferation."

"PI3K is the most commonly mutated pathway in that can be targeted by drugs. Thus, understanding how the pathway and mutations in cancer affect the many different cancer lineages is important," said co-author Dr. Gordon Mills, professor of medicine and immunology at MD Anderson Cancer Center.

Previous studies had identified a number of the genes, proteins and processes involved in the PI3K pathway in cells grown in the lab.

"In this study, we have taken what we have learned in the lab regarding how the pathway works and analyzed it together with information about the genes and the proteins present in taken from human patients," Creighton said. "We looked at nearly 11,000 human cancers representing 32 major types. This is the largest study of its kind, and it was possible in part thanks to the Cancer Genome Atlas, a publicly available dataset of genomic changes in 32 types of cancer."

To carry out the complex analysis of this vast amount of data, the research team pulled the resources of experts in cancer protein data, in molecular biology of the pathway, and in the use of powerful analytical tools that provided genomic analysis and integration of the protein data.

The challenge is to know which mutations in cancer are important

To assess which cancer mutations are important, the researchers carried out a comprehensive analysis that allowed them to distinguish which of the altered genes and proteins were more likely to affect the normal function of the PI3K pathway.

"What makes this analysis complex is that there is a large number of gene and protein alterations that can be present in a given patient's tumor, and it is possible that different alterations are present in different patients," Creighton said. "In addition, not all mutations necessarily cause disease. The challenge is to find out which mutations are altering the pathway in a way that can lead to cancer. We hope that one day we will be able to apply this knowledge to personalized medicine."

There were a few surprises in the study.

"For some genes there was previous work indicating they were implicated in this pathway, but we discovered other genes, such as IDH1 and VHL, which had not been typically associated with the pathway in cancer before," Creighton said. "These genes, as well as others that may be discovered in the future, may now be incorporated into the group of genes linked to the PI3K pathway and considered as potential candidates for targeted therapy."

"Finding several cancers and mutations that we didn't know before could activate this pathway supports moving up the priority of testing drugs toward the new mutations found in specific cancer types," said co-author Dr. David Kwiatkowski, professor of medicine at Harvard Medical School and senior physician at Brigham and Women's Hospital and the Dana Farber Cancer Institute.

The future of personalized medicine

"The comprehensive nature of this project that integrates information from multiple levels has the potential to impact patient management and to eventually improve outcomes for the large population of patients with abnormalities in this very important pathway," Mills said.

"This comprehensive approach expands our knowledge regarding which types of cancer this pathway is activated and why, and that's important in terms of thinking about therapies that go after this pathway," Kwiatkowski said.

Imagine the following possible future scenario in a personalized medicine setting: a patient provides a sample of tumor and the physician sends it to a lab that runs a sequencing assay that shows where the genetic changes are located and the type of changes. Then, from the protein data, the team of physicians and scientists can determine which genetic changes are associated with greater activation of the PI3K pathway and which may not. These data would help the team in terms of selecting patients for whom specific drugs may be effective.

Explore further: New subtypes of lung cancer can lead to personalized therapies with better outcome

More information: Cancer Cell (2017). DOI: 10.1016/j.ccell.2017.04.013

Related Stories

New subtypes of lung cancer can lead to personalized therapies with better outcome

October 24, 2016
Personalized therapies can potentially improve the outcomes of patients with lung cancer, but how to best design such an approach is not always clear. A team of scientists from Baylor College of Medicine and the University ...

Largest genomic study on kidney cancer brings hope for more effective treatments

March 14, 2016
Understanding the complexity of cancer is a major goal of the scientific community, and for kidney cancer researchers this goal just got closer. Dr. Chad Creighton, associate professor of medicine and member of the Dan L ...

Researchers gain insight into breast cancer drug resistance

March 24, 2017
Breast cancer's ability to develop resistance to treatment has frustrated researchers and physicians and has thwarted even the latest and greatest targeted therapies. For example, after researchers identified a disease pathway ...

The PI3K protein: A potential new therapeutic target in pancreatic neuroendocrine tumors

June 20, 2016
Researchers at the Institute of Biomedical Investigation of Bellvitge (IDIBELL), led by Dr. Mariona Graupera, have unveiled the potential therapeutic benefit of a selective inhibitior of the PI3-kinase (PI3K) protein in pancreatic ...

New role for an old protein: Cancer causer

September 3, 2015
A protein known to play a role in transporting the molecular contents of normal cells into and out of various intracellular compartments can also turn such cells cancerous by stimulating a key growth-control pathway.

Newly discovered vulnerability in breast tumor cells points to new cancer treatment path

April 18, 2016
Cancer cells often devise ways to survive even in the presence of toxic chemotherapy. Now, a research team led by investigators at Beth Israel Deaconess Medical Center (BIDMC) has found a way to attack a process that tumor ...

Recommended for you

Study tracks evolutionary transition to destructive cancer

February 23, 2018
Evolution describes how all living forms cope with challenges in their environment, as they struggle to persevere against formidable odds. Mutation and selective pressure—cornerstones of Darwin's theory—are the means ...

Putting black skin cancer to sleep—for good

February 22, 2018
An international research team has succeeded in stopping the growth of malignant melanoma by reactivating a protective mechanism that prevents tumor cells from dividing. The team used chemical agents to block the enzymes ...

Cancer risk associated with key epigenetic changes occurring through normal aging process

February 22, 2018
Some scientists have hypothesized that tumor-promoting changes in cells during cancer development—particularly an epigenetic change involving DNA methylation—arise from rogue cells escaping a natural cell deterioration ...

NEJM reports positive results for larotrectinib against TRK-fusion cancer

February 22, 2018
In 2013, the labs of University of Colorado Cancer Center investigator Robert C. Doebele, MD, PhD, and Dana-Farber Cancer Institute investigator Pasi A. Jänne, MD, PhD reported in Nature Medicine the presence of TRK gene ...

New therapeutic gel shows promise against cancerous tumors

February 21, 2018
Scientists at the UNC School of Medicine and NC State have created an injectable gel-like scaffold that can hold combination chemo-immunotherapeutic drugs and deliver them locally to tumors in a sequential manner. The results ...

Five novel genetic changes linked to pancreatic cancer risk

February 21, 2018
In what is believed to be the largest pancreatic cancer genome-wide association study to date, researchers at the Johns Hopkins Kimmel Cancer Center and the National Cancer Institute, and collaborators from over 80 other ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.