Abstract
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. There are many studies and reports on drug resistance
in cancer cells, but comparatively little is known about the underlying
mechanisms. 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
drug 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 report 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 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 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.
Cancer Drug Resistance: 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.
Further Information: 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-ƒÈB 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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