Oncology Drug Development Update Molecular Profiling Redefines The Nature Of Malignancy And Increases The Adoption Of Targeted Therapeutics
Main Category: Cancer / OncologyArticle Date: 20 Feb 2008 - 0:00 PDT
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Identification of novel cancer-related targets and pathways is redefining our understanding of the nature of malignancy. Molecular profiling is prompting new, more detailed classifications of malignancy enabling the development of specific/personalized cancer therapies. Standard classifications involving gross pathologic hallmarks such as stage and grade are now being further augmented by data detailing the overexpression of oncogenes, silencing of tumor suppressors and presence of mutant forms of relevant markers. In each of these cases novel targeted agents and various combination strategies are being investigated based on the specific molecular profiles of cancer subtypes.
Molecular Profiling Improves Classification and Guides Treatment
In breast cancer, for example, classification has been extended to include metastatic sites (bone, brain), expression of HEr2, and hormone receptor status. A recently introduced classification is triple negative (Er-, Pgr- and HEr2-) breast cancer, also known as basal-cell cancer. Other classifications include inflammatory breast cancer and ductal carcinoma in situ. Different treatment strategies are in development for each of these tumor types. Similarly, most other malignancies are also undergoing reclassification based on specific molecular profiles. Elucidation of the role of Kras in the success or failure of EGFr inhibition in the treatment of colorectal cancer exemplifies the recent remarkable achievements that have been made based on molecular profiling. Authoritative cancer agencies are taking notice. The National Comprehensive Cancer Network (NCCN) has begun to incorporate diagnostic, prognostic and pharmacogenomic evaluations in their updated treatment guidelines.
Targeted Agents in Combination are Entering Clinical Trials
The validated association of aggressive disease and the overexpression of HEr2 in any type or stage of breast cancer have created a $4 billion global market for trastuzumab (Herceptin; Genentech) in 2007. Still, nearly 50% of HEr2-positive patients do not respond to trastuzumab, and survival benefits are transient, often lasting under a year. Furthermore, side effects remain a significant problem. Despite these limitations, trastuzumab is the standard of treatment for both early stage and advanced or metastatic disease and is undergoing clinical trials in combination with numerous approved or novel anticancer agents.
Hundreds of clinical trials are underway combining approved targeted therapeutics with every applicable cytotoxic(s) with the goal of achieving incremental benefits. The greater opportunity, however, may lie in combining targeted therapeutics that address different points in one pathway or interacting pathways involved in angiogenesis, metastasis, drug resistance, and tumor growth and survival. This approach has entered the clinic; recently initiated trials are testing combinations of approved targeted therapeutics with each other. The full impact of combining target agents, however, will not be measured until approved and novel agents are combined in hundreds of different combinations for the treatment of hundreds of specific cancer indications.
Future Oncology Series Details ErbB Pathway-targeted Therapeutics
To date, ErbB pathway abnormalities, which occur in a large number of malignancies, have been the most extensively targeted. Currently, there are 7 approved agents targeting this pathway and over 620 clinical trials are ongoing with these agents in various combinations, mostly with cytotoxic agents but also with each other and with selected novel agents under clinical development. In addition to the over 56 ErbB-targeted agents in development (35 in current clinical trials), numerous molecular markers/pathways are being recognized as contributing to the success or failure of the ErbB pathway inhibitors.
New Medicine's Oncology KnowledgeBASE (nm|OK) is a Complete Knowledge Environment in Drug Development in Cancer
Unlike standard drug databases, nm|OK residing at http://www.nmok.net, is designed to specifically provide a fully realized environment reflecting every aspect of drug development in oncology. nm|OK is an edited, inclusive analysis of all aspects of oncology drug development worldwide, including technologies, targets, companies, business affiliations, medical and clinical developments, protocols and results of thousands of clinical trials, and global markets, among others. Currently, nm|OK profiles over 2,000 anticancer agents/technologies in current development (over 4,000 drugs overall) or on the market, more than 1,200 targets implicated in malignancy, and more than 2,000 companies developing/marketing products in the oncology sector. Protocols, interim and final results are presented for thousands of trials, searchable by both novel and approved agents in monotherapy or combination therapy regiments. In addition, nm|OK describes hundreds of diagnostic, prognostic, and theragnostic methodologies and products as they relate to treatment candidate selection, evaluation of the results of clinical trials, and early and accurate detection of disease.
New Medicine, Inc.
http://www.newmedinc.com
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Matchmaking Between Cancer And Cancer Treatment
posted by Gregory D. Pawelski on 20 Feb 2008 at 6:35 pmThe validation standard that private insurance companies is accepting from molecular profiling tests is "accuracy" and not "efficacy." The "bar" has been instantly lowered. No longer will it be essential to prove that the use of a test improves clinical outcomes, all they have to do for these molecular profiling tests is prove that the test has a useful degree of "accuracy."
However, at the same time, the validation standard they want for cell-based profiling tests is "efficacy." The cell-based profiling tests have the same entitlement to be judged by the same validation standard as molecular profiling tests. The combination of measuring morphologic (structural) effects and metabolic (cell metabolism) effects constitutes measuring the "profile" at the whole cell level. It must be noted that both types of tests are just that, "tests" and not treatment.
Cell-based profiling measures the response of the whole cell to drug exposure, using a combination of morphologic and metabolic endpoints. It is measuring at the cell "population" level than at the "single cell" level. The morphologic endpoint information is gathered by examing the state of hundreds of individual cells. The metabolic endpoints measure the combined metabolism of all cells present in the culture.
In theory, a gene expression assay analogous to what a cell-based profile does, would measure 100,000 genes before and after drug exposure. The sort of gene expression assays that are being done measures gene expression in the "resting" state, prior to drug exposure.
With regard to cancer recurrence, cell-based profiling tests do correlate very well with patient survival, by simply looking at the survival of the tumor cells in control cultures, along with the strength of their cell "robustness" in culture and patient survival. The more "robust" the tumor cells in culture, the shorter the patient survival.
Molecular profiling tests, important in order to identify new therapeutic targets and thereby to develop useful drugs, are still years away from working successfully in predicting treatment response for "individual" patients. Perhaps this is because they are performed on dead, preserved cells that were never actually exposed to the drugs whose activity they are trying to assess.
It will never be as effective as the cell "function" method (is the cell being killed regardless of the mechanism), which exists today and is not hampered by the problems associated with gene expression tests (does the cell express a particular target that the drug is supposed to be attacking).
That is because the cell-based profiling measures the net effect of all processes within the cancer, acting with and against each other in real time, and it tests "living" cells actually exposed to drugs and drug combinations of interest.
There should be recognition that matchmaking between cancer and cancer treatment is one area in cancer research and treatment which is deserving of much greater attention and utilization.
There should be an inclusive effort to study and utilize technologies which are based on both the sub-cellular (molecular) level and at the cellular (cell function/cell culture) level.
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