Research may hasten the effort to determine which strains of cancer will eventually become resistant to chemotherapy, paving the way for developing more effective targeted treatments.
Jeremy Chien, PhD
Research by Jeremy Chien, PhD, of the Cancer Biology Program at The University of Kansas may hasten the effort to determine which strains of cancer will eventually become resistant to chemotherapy, paving the way for developing more effective targeted treatments.1With grants from the Department of Defense and the American Cancer Society, Chien and his team are striving to find the genes responsible for resistance to chemotherapy.1
Their innovative system was inspired by early investigations into cancer genomics.1‘Functional genomics’ was pioneered in the 1980s by Robert A. Weinberg, PhD, who discovered the first human oncogenea gene that can cause normal cells to form cancerous tumors.1-3Weinberg et al used genomic DNA, which contains the entire genetic code for a cell that is passed from one generation to the next from tumor cells and infected murine fibroblast 3T3 cells.1,2The fact that these 3T3 cells can reproduce indefinitely without initiating tumor growth helped Weinberg determine which genes are responsible for the cancer-causing abnormal cell growth.1,2
Chien et al are applying this premise but drawing from a larger pool of genetic information.1Using ten tumor samples from patients with chemo-resistant ovarian cancer, they are extracting mRNA, which carries the blueprint of a protein from the cell’s DNA to its ribosomes that drive protein production.1In an interview withTargeted Oncology, Chien said that their current emphasis is on ovarian cancer “because it is a prototypical disease for p53 dysfunction. We are currently focusing on TP53 mutations because TP53 is estimated to be mutated in over 50% of human cancer. So, drugs that exploit TP53 defects are expected to impact several cancer types where TP53 is mutated.” Hence, their findings may have wide-ranging implications.
Reverse Transcription Process
The mRNA from the tumor samples will be converted into cDNA, which is the opposite of what normally occurs (RNA is formed from DNA).1Chien is using the reverse transcription process because he “wants to express a specific protein in a cell that does not normally express in that protein.”1
A Toolkit to Combat Cancer
The new cDNA is placed in a cDNA expressing library.1Here, the cDNA is put into host cells, and “all together they contain the RNA from the original tumor samples.”1Aptly, Chien calls this a “genome-wide cancer toolkit.”1He said that the kit can be used to identify cancer genes that cause the transformed phenotype, that promote metastatic phenotypes, or that cause resistance to drug treatment.1The team’s current focus is drug resistance, so they are searching for the appropriate phenotype.1
Once the DNA library has been created, Chien et al will introduce the cDNA into an ovarian cancer cell that is normally sensitive to chemotherapy.1They plan to test two types of chemotherapy commonly used for ovarian cancer: carboplatin and taxol.1Cells that demonstrate resistance to treatment will be extracted, and the gene within can be sequenced and identified as being chemo-resistant.1
Once the genes responsible for chemo-resistance have been identified, Chien and his team will test current and new drugs aimed at targeting the culprit genes, giving hope to patients who cannot be treated successfully with standard therapies.1He is already enthused about potential treatment options for a candidate gene in the toolkit that “may play a role in taxol resistance, which happens to have a drug that can inhibit that gene,” he said. He also added that “It’s already out there being used to treat another disease; it just hasn’t yet been tested in treating ovarian cancer.”1He noted that if a drug exists to combat the candidate genes, “we will start using it to treat cancer. Otherwise, we will develop new drugs to target them.”1
Informing the Future of Targeted Therapy
Identifying these genes is a critical step in targeting them to reverse chemotherapy resistance or to make chemotherapy more effective, said Chien.1“As we move toward precision cancer medicine, there is an increasing emphasis on genetically based clinical trials that exploit genetic vulnerabilities and oncogene addiction in cancer for therapeutic benefits,” explained Chien in the interview. “At a fundamental level, we are looking to understand the genetic basis for chemotherapy resistance, and [gain] better understanding of tumor-intrinsic genetic factors that contribute to chemotherapy resistance. This will allow us to develop targeted therapies that restore sensitivity to chemotherapy or extend the durability of current chemotherapies,” he said.
On the Horizon
A future goal for Chien’s research program is to develop “rational combinations of cancer therapies that exploit genetic defects and harness the power of the immune system with immunotherapies,” said Chien. His team plans to investigate drugs that target biological pathways activated by TP53 that also have the ability to enhance tumor immunity.
1. The University of Kansas Cancer Center. Rewriting the book on chemo-resistant cancers with a DNA library [press release]. http://www.newswise.com/articles/view/635003/?sc=mwhr&xy=10013055. Accessed July 10, 2015.
2. MIT Whitehead Institute. Faculty information: Robert A. Weinberg. http://wi.mit.edu/people/faculty/weinberg. Accessed July 11, 2015.
3. McCoy MS, Toole JJ, Cunningham JM, Change EH, Lowy DR, Weinberg RA. Characterization of a human colon/lung carcinoma oncogene.Nature.1983;302(5903):79-81.