HER2 Support Group Forums - View Single Post - Why Do Some Breast Cancers Stop Responding to Targeted Therapy?

gdpawel · 03-02-2008, 12:03 AM

Thank you for the link to Dr. Osborne's presentation at the Miami Breast Cancer Conference in Orlando. The underlying assumption in this presentation has been that the pathways of tumor cells can be known in sufficient detail to control cancer. This assumption is embedded in the approach described in this and other presentations in the past.

Sequencing the genome of cancer cells is explicitly based upon this assumption, an assumption that just so happens to be false. The assumption that the pathways of tumor cells can be known in a patient with metastatic cancer is logically inconsistent with the reality of tumor cell evolution. The problem is that a patient with metastatic cancer can have billions of unknown cancer cells disseminated throughout the body at unknown locations. Each cancer cell can be different. And the cancer cells that are present change and evolve with time.

The required target for the consistent and specific control of cancer is the set of all malignant cells that could evolve. Targeting a lesser set will fail. It may act to change the course, but not the flow of tumor cell evolution. It must have the ability to kill or inactivate all malignant cells in the patient (one malignant cell that excapes could multiply and cause progressive disease). It must have the ability to target cancer cells without harming normal cells or causing toxicity to the patient, and target properties of cancer that can be known, or accurately predicted.

The consistent and specific control of cancer will require a set of drugs, given in combination, targeted to patterns of normal cellular machinery related to proliferation and invasiveness. A sufficient number of independent methods of cell killing must be employed so that it is too improbable for cancer cells to evolve that can escape death or inactivation. It must examine functional aspects of every cell in the body and must do so for a prolonged period of time.

Today, we have the ability to take a cancer specimen, analyze it, and follow those genetic changes that influence particular pathways, then use two, three, four or more targeted therapies, perhaps simultaneously, and be able to completely interrupt the flow of the cancer process.

Given the current state of the art, in vitro drug resistance and sensitivity testing could be of significant clinical value to this premise. If in vitro drug resistance can demonstrate the presence of cancer cells that are resistant to a drug combination, then it would be rational to use alternative therapy. If in vitro drug sensitivity can demonstrate which drug combinations would be synergistic to cell death in all cancer cells present, then it would be rational to use the drugs indicated in the assay.

Functional profiling assays can assess the activity of a drug combination upon combined effect of all cellular processes, using combined metabolic (cell metabolism) and morphologic (structure) endpoints, at the cell population level, measuring the interaction of the entire genome.

Functional, cell culture-based assays are vastly more informative for virtually all drugs than marker-based tests, including multi-gene tests. Functional assays are the best available tests in the world for anti-vascular drugs, such as Avastin, Sutent, Nexavar, Tarceva, Iressa, Tykerb, Gleevec, Tamoxifen, Thalidomide, etc., both as single agents and in combination with each other and with traditional cytotoxic agents.

Functional assays can provide more valuable information today than will be provided with marker and genomic-based assays ten years from now. It simultaneously tests for direct anti-tumor activity and for anti-vascular activity against the microvascular present within the three-dimensional tumor cell clusters.

A number of cell culture assay labs across the country have data from tens of thousands of fresh human tumor specimens, representing virtually all types of human solid and hematologic neoplasms. Cell culture assay labs have the database necessary to define sensitivity and resistance for virtually all of the currently available drugs in virtually all types of human solid and hematologic neoplasms.

Literature Citation:

Eur J Clin Invest 37 (suppl. 1):60, 2007

Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 17117

"Cure: Scientific, Social, and Organizational Requirements for the Specific Cure of Cancer" A. Glazier, et al.

03-02-2008, 12:03 AM	#3
gdpawel Senior Member Join Date: Aug 2006 Location: Pennsylvania Posts: 1,080	Logical Implications of Tumor Cell Evolution Thank you for the link to Dr. Osborne's presentation at the Miami Breast Cancer Conference in Orlando. The underlying assumption in this presentation has been that the pathways of tumor cells can be known in sufficient detail to control cancer. This assumption is embedded in the approach described in this and other presentations in the past. Sequencing the genome of cancer cells is explicitly based upon this assumption, an assumption that just so happens to be false. The assumption that the pathways of tumor cells can be known in a patient with metastatic cancer is logically inconsistent with the reality of tumor cell evolution. The problem is that a patient with metastatic cancer can have billions of unknown cancer cells disseminated throughout the body at unknown locations. Each cancer cell can be different. And the cancer cells that are present change and evolve with time. The required target for the consistent and specific control of cancer is the set of all malignant cells that could evolve. Targeting a lesser set will fail. It may act to change the course, but not the flow of tumor cell evolution. It must have the ability to kill or inactivate all malignant cells in the patient (one malignant cell that excapes could multiply and cause progressive disease). It must have the ability to target cancer cells without harming normal cells or causing toxicity to the patient, and target properties of cancer that can be known, or accurately predicted. The consistent and specific control of cancer will require a set of drugs, given in combination, targeted to patterns of normal cellular machinery related to proliferation and invasiveness. A sufficient number of independent methods of cell killing must be employed so that it is too improbable for cancer cells to evolve that can escape death or inactivation. It must examine functional aspects of every cell in the body and must do so for a prolonged period of time. Today, we have the ability to take a cancer specimen, analyze it, and follow those genetic changes that influence particular pathways, then use two, three, four or more targeted therapies, perhaps simultaneously, and be able to completely interrupt the flow of the cancer process. Given the current state of the art, in vitro drug resistance and sensitivity testing could be of significant clinical value to this premise. If in vitro drug resistance can demonstrate the presence of cancer cells that are resistant to a drug combination, then it would be rational to use alternative therapy. If in vitro drug sensitivity can demonstrate which drug combinations would be synergistic to cell death in all cancer cells present, then it would be rational to use the drugs indicated in the assay. Functional profiling assays can assess the activity of a drug combination upon combined effect of all cellular processes, using combined metabolic (cell metabolism) and morphologic (structure) endpoints, at the cell population level, measuring the interaction of the entire genome. Functional, cell culture-based assays are vastly more informative for virtually all drugs than marker-based tests, including multi-gene tests. Functional assays are the best available tests in the world for anti-vascular drugs, such as Avastin, Sutent, Nexavar, Tarceva, Iressa, Tykerb, Gleevec, Tamoxifen, Thalidomide, etc., both as single agents and in combination with each other and with traditional cytotoxic agents. Functional assays can provide more valuable information today than will be provided with marker and genomic-based assays ten years from now. It simultaneously tests for direct anti-tumor activity and for anti-vascular activity against the microvascular present within the three-dimensional tumor cell clusters. A number of cell culture assay labs across the country have data from tens of thousands of fresh human tumor specimens, representing virtually all types of human solid and hematologic neoplasms. Cell culture assay labs have the database necessary to define sensitivity and resistance for virtually all of the currently available drugs in virtually all types of human solid and hematologic neoplasms. Literature Citation: Eur J Clin Invest 37 (suppl. 1):60, 2007 Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 17117 "Cure: Scientific, Social, and Organizational Requirements for the Specific Cure of Cancer" A. Glazier, et al.