Rewriting the book on chemotherapy-resistance in cancers with a "genome-wide cancer toolkit"

Determining which cancer cells will eventually become resistant to chemotherapy could be key in figuring out more effective and targeted forms of treatment. Finding the genes responsible for chemotherapy-resistance is what Jeremy Chien, Ph.D., member of the Cancer Biology Program at The University of Kansas Cancer Center, is looking to do with an innovative system that draws inspiration from the early days of research in cancer gene discoveries.

Two grants from the Department of Defense and the American Cancer Society will bolster his ongoing research into finding out why ovarian cancer becomes resistant to conventional chemo and eventually identifying a different drug target. Success in these approaches would mean having a type of chemotherapy resistant cancer would no longer be seen as an almost insurmountable roadblock in treating cancer. He's doing this by creating what he calls a "genome-wide cancer toolkit" to determine which genes contribute to drug resistance.

"Our research focuses on the identification of "driver" genes in ovarian cancer," Dr. Chien said. "In particular, we are interested in identifying genes that make cancer cells resistant to chemotherapy. Identifying these genes is a critical first step in targeting them to reverse chemotherapy resistance."

Dr. Chien is one of few researchers working to create this particular kind of database for specific types of ovarian cancer and by collecting a library of genes expressed in chemo-resistant ovarian cancers. He noted other researchers are also building limited libraries, such as libraries of mutations in a class of proteins called tyrosine kinases, which are focused just on those enzymes responsible for activating proteins. Many cancers with these mutations can be treated with tyrosine kinase inhibitors; however, some mutations develop a resistance to inhibitor treatment.

His toolkit aims to look at a more comprehensive set of genes expressed in chemotherapy resistant-ovarian cancer, in this case, and figure out which genes are responsible for chemo resistance.

Drawing from genetic history

"Functional genomics" was first used in the early 1980s by Dr. Robert Weinberg, who discovered the first human oncogene - a gene that has the potential to cause cancer. Dr. Weinberg and his team used genomic DNA from cancer cells. They isolated the DNA from cancer cells, which would include mutated genetic codes, and introduced them into non-cancer cells. Dr. Weinberg and his team were able to determine which introduced genes were responsible for abnormal cell growth.

Dr. Chien is using the same premise, but drawing from a wider pool of genetic information. His lab instead extracted mRNA, which carries the blueprint of proteins that create cell behavior, from 10 tumor samples of patients with chemo resistant ovarian cancer.

Dr. Chien takes the mRNA from those tumor samples and then converts it into cDNA. This process, called reverse transcription, allows blueprints of expressed genes to be converted back into genes. This produces specific proteins originally expressed in the tumor samples.

He calls this collection of genes a "genome-wide cancer toolkit."

"It can be used to identify cancer genes that caused various cancer phenotypes, those that promoted metastasis or those that promoted drug resistance," Dr. Chien said. "In our case, the phenotype we are looking for is drug-resistance, so we are interested in the specific genes that contribute to drug resistance."

After the library's creation, Dr. Chien can introduce the cancer-derived cDNA into ovarian cancer cell lines normally sensitive to chemo. From there, he is testing two types of chemotherapy commonly used to treat ovarian cancer, carboplatin and Taxol. After the treatment, the cells that became resistant to the drugs are collected and the gene within the resistant cells can be sequenced and identified as genes that produce chemo resistance.

From DNA to drug testing

The information collected from the cancer toolkit may be relevant to more than just helping treat ovarian cancer.

One of the major gene mutations found in ovarian cancer is in the p53 tumor suppressor gene, which is also mutated in approximately 50 percent of other human cancers. Dr. Chien knows a lot of these p53 mutations will be found in their library and could also be involved in chemotherapy resistance.

"So potentially whatever we find in regard to p53 may be applicable to other cancers," he said.

After identifying the genes responsible for chemo-resistance, Dr. Chien can test already existing drugs or new therapies aimed at targeting these specific genes and give hope to people who cannot be treated successfully with the standard treatments.

He's already excited about the potential treatment options for one candidate gene found in the toolkit.

"We found a gene that may play a role in Taxol resistance, which also happens to have a FDA-approved drug that can inhibit the gene product," says Dr. Chien. "It's already out there being used to treat another disease; it just hasn't yet been tested in treating cancer.

"That is our hope—if we have a known drug for the chemotherapy resistant genes, we could start using it to treat cancer. Otherwise we will develop new drugs to target them."

Funding

  • Department of Defense Ovarian Cancer Academy Program
  • National Science Foundation
  • American Cancer Society

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