HER2 Support Group Forums - View Single Post - Brighton researchers' discovery may prolong cancer patients

gdpawel · 05-18-2013, 08:40 AM

When it comes to anticancer drugs, not all patients respond alike. Some of the variation among patients in both response and toxicity associated with anticancer therapy is due to a patient's genetic makeup.

A new review provides an overview on the progress made in studies of pharmacogenetics and pharmacogenomics, which have successfully identified genetic variants that contribute to this variation in susceptibility to chemotherapy.

The authors say technological advances make it feasible to evaluate the human genome in a relatively inexpensive and efficient manner, but that extensive research and education are urgently needed to improve the translation of pharmacogenetic concepts from bench to bedside (CA Cancer J Clin 2009;59:42-55).

The basic definition of pharmacogenetics is the use of genetic information to help in the therapeutic treatment of a disease. Pharmacogenomics, on the other hand, can be defined as the study of how a person's genetic makeup determines response to a drug.

The terms pharmacogenomics and pharmacogenetics are often used interchangeably to describe a field of research focused on how genes affect individual responses to medicines. Whether a medicine works well for you—or whether it causes serious side effects—depends, to a certain extent, on your genes.

Just as genes contribute to whether you will be tall or short, black-haired or blond, your genes also determine how you will respond to medicines. Genes are like recipes—they carry instructions for making protein molecules. As medicines travel through your body, they interact with thousands of proteins. Small differences in the composition or quantities of these molecules can affect how medicines do their jobs.

These differences can be due to diet, level of activity, or the medicines a person takes, but they can also be due to differences in genes. By understanding the genetic basis of drug responses, scientists hope to enable doctors to prescribe the drugs and doses best suited for each individual. The right drug—for cancer.

Pharmacogenetics is used in targeted therapy for cancer to identify the best drug regimen for a particular tumor. Even tumors of the same type (such as lung, breast, or liver) vary at the genetic level. Cancer is fundamentally a genetic disease, but most of the genetic differences between cancer cells and normal cells are not inherited—they accumulate as the cancer develops. Analyzing specific genes in a patient’s tumor helps doctors identify the drug combination to which the tumor will most likely respond.

For example, the breast cancer drug Herceptin is only effective when the tumor cells have accumulated extra copies of the HER2 gene and have high levels of the protein this gene encodes on their surfaces. Cancer biopsy samples are also often subjected to genetic tests. The results can help guide therapy and predict the likelihood of recurrence.

A challenge facing pharmacogenetics is the number and complexity of interactions a drug has with biological molecules in the body. Variations in many different molecules may influence how someone responds to a medicine. Teasing out the genetic patterns associated with particular drug responses could involve some intricate and time-consuming scientific detective work.

Several new "targeted" drugs have been introduced during the last few years. Most of them have been developed for use in solid tumors but some have also emerged for hematological maligancies. These new "targeted" drugs mostly need to be combined with active chemotherapy to provide any benefit and the need for predictive tests for individualized therapy selection has increased.

Unfortunately, the introduction of these new drugs has not been accompanied by specific predictive tests allowing for a rational and economical use of the drugs. Drugmakers had said that pharmacogenetics will not change the landscape for the bulk of pharmaceuticals for several years. Pharmacogenetics is not going to transform the market any time soon.

There are a number of laboratory tests that are better able to predict the ability of targeted drugs, to produce positive clinical responders (outcomes). Given the technical and conceptual advantages of Oncologic In Vitro Chemoresponse Assays, together with their performance and the modest efficacy of therapy prediction based on analysis of genome expression, there is reason for a renewal in the interest for Oncologic In Vitro Chemoresponse Assays for optimized use of medical treatment of malignant disease.

Over the past few years, gene expression profiling has been suggested as the best or only way of determining ex vivo drug sensitivity. However, the clinical application of these DNA content assays have been shown to correlate only with response and not survival. And due to almost all patients being treated with combination chemotherapy, this methodology cannot even be calibrated without the use of Oncologic In Vitro Chemoresponse Assays. These assays can actually integrate all the gene expression into one convenient test result.

In obtaining information from gene mutations (DNA content assays) and/or gene expression (RNA content) it must be realized that DNA structure is only important insofar as it predicts for RNA content, which is only important insofar as it predicts for protein content, which is only important insofar as it predicts for protein function, which is important only insofar as it predicts for cell response, which is only important insofar as it predicts for tumor response and function. In other words, it correlates only with response and not survival, in entirely retrospective (not prospective) studies.

Patients, physicians, insurance carriers, and the FDA are all calling for predictive tests that allow for rational and cost-effective use of these drugs. You will find it with Oncologic In Vitro Chemoresponse Assays, testing for drug activity against a tumor. What a cancer patient would like ideally, is an active drug, one that will be beneficial the first time around.

By testing the tumor cells of a cancer patient and testing the patient toxicity tolerance, the oncologist can select drugs that have a higher probability of being effective for an individual patient rather than selecting drugs based on the average responses of many patients in large clinical trials.

Literature Citation:

Weisenthal, L.M. Functional profiling with cell culture-based assays for kinase and anti-angiogenic agents Eur J Clin Invest 37 (suppl. 1):60, 2007

Nagourney, R.A. Functional Profiling of Human Tumors in Primary Culture: A Platform for Drug Discovery and Therapy Selection (AACR: Apr 2008-AB-1546)

05-18-2013, 08:40 AM	#6
gdpawel Senior Member Join Date: Aug 2006 Location: Pennsylvania Posts: 1,080	Pharmacogenetics of Anticancer Agents When it comes to anticancer drugs, not all patients respond alike. Some of the variation among patients in both response and toxicity associated with anticancer therapy is due to a patient's genetic makeup. A new review provides an overview on the progress made in studies of pharmacogenetics and pharmacogenomics, which have successfully identified genetic variants that contribute to this variation in susceptibility to chemotherapy. The authors say technological advances make it feasible to evaluate the human genome in a relatively inexpensive and efficient manner, but that extensive research and education are urgently needed to improve the translation of pharmacogenetic concepts from bench to bedside (CA Cancer J Clin 2009;59:42-55). The basic definition of pharmacogenetics is the use of genetic information to help in the therapeutic treatment of a disease. Pharmacogenomics, on the other hand, can be defined as the study of how a person's genetic makeup determines response to a drug. The terms pharmacogenomics and pharmacogenetics are often used interchangeably to describe a field of research focused on how genes affect individual responses to medicines. Whether a medicine works well for you—or whether it causes serious side effects—depends, to a certain extent, on your genes. Just as genes contribute to whether you will be tall or short, black-haired or blond, your genes also determine how you will respond to medicines. Genes are like recipes—they carry instructions for making protein molecules. As medicines travel through your body, they interact with thousands of proteins. Small differences in the composition or quantities of these molecules can affect how medicines do their jobs. These differences can be due to diet, level of activity, or the medicines a person takes, but they can also be due to differences in genes. By understanding the genetic basis of drug responses, scientists hope to enable doctors to prescribe the drugs and doses best suited for each individual. The right drug—for cancer. Pharmacogenetics is used in targeted therapy for cancer to identify the best drug regimen for a particular tumor. Even tumors of the same type (such as lung, breast, or liver) vary at the genetic level. Cancer is fundamentally a genetic disease, but most of the genetic differences between cancer cells and normal cells are not inherited—they accumulate as the cancer develops. Analyzing specific genes in a patient’s tumor helps doctors identify the drug combination to which the tumor will most likely respond. For example, the breast cancer drug Herceptin is only effective when the tumor cells have accumulated extra copies of the HER2 gene and have high levels of the protein this gene encodes on their surfaces. Cancer biopsy samples are also often subjected to genetic tests. The results can help guide therapy and predict the likelihood of recurrence. A challenge facing pharmacogenetics is the number and complexity of interactions a drug has with biological molecules in the body. Variations in many different molecules may influence how someone responds to a medicine. Teasing out the genetic patterns associated with particular drug responses could involve some intricate and time-consuming scientific detective work. Several new "targeted" drugs have been introduced during the last few years. Most of them have been developed for use in solid tumors but some have also emerged for hematological maligancies. These new "targeted" drugs mostly need to be combined with active chemotherapy to provide any benefit and the need for predictive tests for individualized therapy selection has increased. Unfortunately, the introduction of these new drugs has not been accompanied by specific predictive tests allowing for a rational and economical use of the drugs. Drugmakers had said that pharmacogenetics will not change the landscape for the bulk of pharmaceuticals for several years. Pharmacogenetics is not going to transform the market any time soon. There are a number of laboratory tests that are better able to predict the ability of targeted drugs, to produce positive clinical responders (outcomes). Given the technical and conceptual advantages of Oncologic In Vitro Chemoresponse Assays, together with their performance and the modest efficacy of therapy prediction based on analysis of genome expression, there is reason for a renewal in the interest for Oncologic In Vitro Chemoresponse Assays for optimized use of medical treatment of malignant disease. Over the past few years, gene expression profiling has been suggested as the best or only way of determining ex vivo drug sensitivity. However, the clinical application of these DNA content assays have been shown to correlate only with response and not survival. And due to almost all patients being treated with combination chemotherapy, this methodology cannot even be calibrated without the use of Oncologic In Vitro Chemoresponse Assays. These assays can actually integrate all the gene expression into one convenient test result. In obtaining information from gene mutations (DNA content assays) and/or gene expression (RNA content) it must be realized that DNA structure is only important insofar as it predicts for RNA content, which is only important insofar as it predicts for protein content, which is only important insofar as it predicts for protein function, which is important only insofar as it predicts for cell response, which is only important insofar as it predicts for tumor response and function. In other words, it correlates only with response and not survival, in entirely retrospective (not prospective) studies. Patients, physicians, insurance carriers, and the FDA are all calling for predictive tests that allow for rational and cost-effective use of these drugs. You will find it with Oncologic In Vitro Chemoresponse Assays, testing for drug activity against a tumor. What a cancer patient would like ideally, is an active drug, one that will be beneficial the first time around. By testing the tumor cells of a cancer patient and testing the patient toxicity tolerance, the oncologist can select drugs that have a higher probability of being effective for an individual patient rather than selecting drugs based on the average responses of many patients in large clinical trials. Literature Citation: Weisenthal, L.M. Functional profiling with cell culture-based assays for kinase and anti-angiogenic agents Eur J Clin Invest 37 (suppl. 1):60, 2007 Nagourney, R.A. Functional Profiling of Human Tumors in Primary Culture: A Platform for Drug Discovery and Therapy Selection (AACR: Apr 2008-AB-1546)