Why Chemo Works For Some People And Not Others - MIT Cell Findings Could Predict Individuals’ Responses
MIT researchers have shown that cells from different people don’t all react the same way when exposed to the same DNA-damaging agent - a finding that could help clinicians predict how patients will respond to chemotherapy.
The research team from MIT’s Center for Environmental Health Sciences (CEHS) and the Departments of Biological Engineering and Biology, identified a group of 48 genes that can predict how susceptible an individual is to the toxic compound, known as MNNG. The work appears in the Sept. 19 online edition of Genes and Development.
MNNG, a DNA-damaging compound similar to toxic chemicals found in tobacco smoke and in common chemotherapy agents, usually kills cells by inducing irreparable DNA damage. However, the researchers found a wide range of susceptibility among cells taken from healthy people.
“A cell line from one person would be killed dramatically, while that from another person was resistant to exposure,” said Rebecca Fry, former MIT research scientist and lead author of the paper. “It wasn’t known that cell lines from different people could have such dramatic differences in responses.”
Toxic agents such as MNNG create lesions in DNA, provoking the cell to defend itself with a variety of DNA-repair and other pathways. However, every individual expresses slight differences in the genes involved in those pathways.
“Even if everyone is exposed to exactly the same things, they would respond differently, because we’re all genetically different,” said Leona Samson, senior author of the paper, director of CEHS, and an American Cancer Society Research Professor.
The team members found that after measuring the expression of every gene in each cell line, they could predict cell sensitivity to MNNG from the expression of just 48 specific genes, with 94 percent accuracy.
Several of those 48 genes have already been linked to cancer, said Samson, but it was not known that their expression is already altered before exposure to the DNA damaging agent.
This study is specific to MNNG, but similar efforts are now underway in Samson’s lab to predict individuals’ responses to other toxic agents, including cisplatin, a common chemotherapy agent, and temozolomide, used to treat brain cancer.
Fry, the lead author of the paper, is now an assistant professor at the University of North Carolina School of Public Health. Other authors are Peter Svensson, a postdoctoral fellow in CEHS; Chandni Valiathan, a graduate student in computational and systems biology; Emma Wang and Brad Hogan, technical assistants in CEHS; Sanchita Bhattacharya, former CEHS research scientist; James Bugni, former CEHS postdoctoral fellow; and Charles Whittaker, a research scientist in the David H. Koch Institute for Integrative Cancer Research.
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October 7th, 2008 at 8:21 am
There is a headlong rush to develop tests to identify molecular predisposing mechanisms, whose presence still does not guarantee that a drug will be effective for an individual patient. Nor can they, for any patient or even large group of patients, discriminate the potential for clinical activity among different agents of the same class.
The challenge is to identify which patients targeted treatment will be most effective. Tumors can become resistant to a targeted treatment, or the drug no longer works, even if it has previously been effective in shrinking a tumor. Drugs are combined with existing ones to target the tumor more effectively. Most cancers cannot be effectively treated with targeted drugs alone.
Paraffin embedded, fixed, minced, or frozen tissue can change over time. One gets more accurate information when using intact RNA isolated from “fresh” living tissue than from using degraded RNA, which is present in paraffin-fixed tissue.
Established cell line is not reflective of the behavior of fresh tumor cells in primary culture in the lab, much less in the patient. You get different results when you test passaged cells compared to primary, fresh tumors. Molecular testing methods detect the presence or absence of selected gene mutations which theoretically correlate with single agent drug activity. Cells are never exposed to anti-cancer agents.
What is needed is to measure the net effect of all processes within the cancer, acting with and against each other in real time, and test living cells actually exposed to drugs and drug combinations of interest. The key to understanding the genome is understanding how cells work. How is the cell being killed regardless of the mechanism?
Cell culture testing methods assess the net effect of all inter-cellular and intra-cellular processes occurring in real time when cells are exposed to anti-cancer agents. Tests are performed using intact, living cancer cells plated in 3D microclusters. It allows for testing of different drugs within the same class and drug combinations to detect drug synergy and drug antagonism.
The core understanding is the cell, composed of hundreds of complex molecules that regulate the pathways necessary for vital cellular functions. If a targeted drug could perturb any of these pathways, it is important to examine the effects of drug combinations within the context of the cell.
Both genomics and proteomics can identify potential therapeutic targets, but these targets require the determination of cellular endpoints. You still need to measure the net effect of all processes, not just the individual molecular targets.
Literature Citation:
Eur J Clin Invest, Volume 37(suppl. 1):60, April 2007
BMJ 2007;334(suppl 1):s18 (6 January), doi:10.1136/bmj.39034.719942.94