Cancer Drug Resistance 2008
Resistance Mechanisms, Resistance Biomarkers, Current & Pipeline Cancer Drugs and Strategies to Combat Drug Resistance
Drug resistance is the single most important cause of cancer treatment failure and carries a massive burden to patients, healthcare providers, drug developers and society. It is estimated that Multidrug Resistance (MDR) plays a major role in up to 50% of cancer cases. Today, most drug therapies involve multiple agents, as it is almost universally the case that single drugs (or single-target drugs) will encounter resistance.
Drug resistance presents some of the greatest challenges to the treatment and eradication of cancer. This report brings together much of what is known and understood on drug resistance into one place, giving the reader access to a significant body of knowledge and an analysis of current developments, limitations, challenges, innovation and trends in this important field. This includes a comprehensive review of resistance-associated changes and mechanisms for all approved cancer drugs (60 drug classes) and Phase III candidates, as well as an examination of how developers are tackling drugs resistance using novel agents and new drug combinations. This report looks at every general class of cancer drug in the pipeline or launched (around 400, representing 2000+ agents) and has identified all new drug classes from Preclinical through to Phase III, that will provide new strategies to tackle resistance. The entire cancer drug development pipeline is also tabulated, allowing the reader to compare current drug classes alongside new classes coming through the pipeline. This report provides a comprehensive and up-to-date review of cancer resistance today and the strategies being developed to combat these mechanisms.
This new 2008 report presents a detailed review of cancer drug resistance today and includes
i) A Global Resistance Map: a presentation and review of resistance mechanisms or resistance-associated changes at the gene, protein or functional level reported for currently approved cancer drugs, covering 60 general cancer drug classes and 190 agents
ii) Drug Pipeline: a presentation of the entire anticancer drug development pipeline (2000+ agents from approx. 400 general drug classes), from preclinical to launched, including mechanisms of action of individual drugs. This pipeline not only provides an excellent tool for all involved in monitoring oncology research and development but it is also of importance to the present report as it maps out those candidates with which drug resistance strategies will have to integrate
iii) New Drug Mechanisms: new cancer agents in the development pipeline (i.e. drug mechanisms not previously developed in any previous drug development phase), representing 157, 56, 84 and 37 new drug classes at preclinical, phase I, phase II and phase III, respectively. All phase III candidates are evaluated in terms of drug resistance susceptibility
iv) Strategies to Combat Cancer Drug Resistance: including targeting, bypassing or exploiting resistance mechanisms, current and new drug combinations and novel drugs offering new ways to target drug resistance.
v) Resistance Biomarkers: a presentation of current findings at the gene and/or protein level for all currently launched anticancer drugs, that offer potential resistance biomarkers for drug discovery, diagnostics and therapy decisions
Anticancer drugs fail to kill cancer cells for a number of reasons. These include kinetic factors, where drugs fail to reach tumours, are poorly absorbed or metabolically deactivated. Drug resistance mechanisms are either innate, where they are intrinsic to the cancer or acquired, which occurs due to adaptive changes in response to therapy and due to the selection of survival phenotypes. Today, new drug combinations are central to the strategy to combat resistance and this report estimates (from trials in the US & UK) that 40-50% of current cancer drug trials involve multiple drug combinations. These include combinations of established small molecule drugs with others, with new agents or with immunotherapeutic molecules.
Targeting Resistance Mechanisms: Advancing knowledge at the gene and protein level in cancer cells is enabling scientists to better understand interconnected pathways involved cell cycle control, cell signaling and cell death and this is enabling viability-critical targets or target combinations to be more readily identified. In developing new combination drug therapies, a key goal is to identify targets that together represent an Achilles Heel to the cell. For example, scientists have reported that BRCA1 or BRCA2 mutant cells, which show defective DNA maintenance, are very sensitive to inhibitors of another genome maintenance pathway. These studies showed that inhibitors of the enzyme PARP (Poly(ADP-Ribose) polymerase) are able to kill cells that are defective in BRCA1 or BRCA2 at very low concentrations, compared to normal cancer cells. This illustrates the potential of targeting co-supportive or co-dependent pathways. Resistance data (at the gene and protein level), cited in this report, provides a comprehensive and detailed update of scientists’ findings on cancer drug resistance, to assist efforts to better understand and target the associated mechanisms.
This report also reviews all current phase III anticancer drugs, focusing on novel drug classes that are creating interest in their potential to combat drug resistance. This includes immunotherapeutic drugs (500+ agents in development or launched), second-generation targeted therapies (i.e. multi-target drugs; 15+ prominent candidates in development) and other drug classes such as the NF-κB inhibitors (30+candidates in development), heat shock protein inhibitors (40+ candidates in development), HDAC inhibitors and many others.
This report also includes an in-depth discussion with Michael M. Gottesman M.D. (Head, Molecular Cell Genetics, Multidrug Resistance Unit, Centre for Cancer Research, US National Cancer Institute) and cites more than 260 References
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