Pepmoron Exposedhttps://www.tau.ac.il/lifesci/departments/neuro/members/kloog/documents/blum.pdf
Pepmoron thinks you are dumb asss moron, he thinks you will never understand the above.
I think this dated paper of 2005 is a good paper. Most of what was speculated is happening rigth here right now at ASCO 2009.
Papers says - RAS inbitor is a combo for all treatment. Probably the new standard of care.
4601 blocks all downsteam events, this is the holy grail of RAS.
If you read the conclusion of the paper, you cannot be more exited!
-KRAS has been identified
-There KRAS diagnostic tools
- 232 and 4601 are the prefered combo according to the author
-Drug combo era has started... IRessa/Tarceva + 4601
-talks about biomarker use, well isn,'t that Caprion?
8. Looking ahead
The partial success in clinical trials with Ras pathway
inhibitors, alone or in various combinations with classic therapies,
suggests that it would be possible to tailor drug combinations
having a significantly higher potential for killing
of tumor cells with minimal effects on normal cells. Such
tailoring is already possible because of increased knowledge
of the complexity of Ras pathways, their cooperation with
other oncogenic pathways, and their “addictive” nature. We
have provided a number of examples demonstrating that such
knowledge can be translated into a useful drug combination,
which disrupts multiple oncogenic pathways and hits a weak
point of a given tumor cell; for example, combined treatment
with a Ras inhibitor and a glycolysis blocker kills pancreatic
tumor cells. This is only one of many possibilities that can be
exploited for tailored cancer therapy with existing drugs that
target well-known oncogenic pathways. The design of such
drug-combination therapies and the follow-up of their outcome
will undoubtedly be facilitated by the use of biological
markers, gene expression profiling and proteomic methods.
Biological markers have a number of benefits. First, they
can be used as quantifiable measures of the oncogenic cascade
(Garcea et al., 2005; Ghaneh et al., 2002). Second, prognostic
biological markers may become potential targets for drug
treatment in themselves. Third, biological markers can be
used as surrogate markers in tumor or in other tissues such
as sera. This allows recording progression of the tumors or
their response to drugs. Last, biological markers can be used
for early diagnosis or for the identification of patients at-risk
of cancer development (Garcea et al., 2005; Ghaneh et al.,
2002).
Proteomics should provide a convenient platform for validating
the efficacy of investigated drug combinations. In
addition, the microarray technologies should make it possible
to determine gene expression patterns before and after
a single drug treatment or drug combination (Herbst et al.,
2005a; Johnson et al., 2004).
Critical for the success of this technique is the identification
of genes involved in conferring drug sensitivity and
resistance, as well as predicting which patients are most likely
to benefit from the drug treatment. Thanks to recent improvements
in computational methods for promoter sequence analysis
(Elkon et al., 2003) and the integration of “metagene”
analysis to predict the activity of oncogenic pathways (Huang
et al., 2003), we can now track down the activation status of
key transcription factors that govern specific gene expression.
This dramatically improves our ability to find a gene product
that is critical for the survival of a given tumor cell but
is less important for the normal cell. The use of microarrays
also generates
database sets that should allow confirmation
of the mechanism of action of a given drug. This technology
is likely to play an important role in all phases of drug
discovery and development. It includes identification and validation
of new targets, profiling of on- and off-target effects
during optimization of new drugs and of drug combinations,
and prediction of side effects. In our laboratory we are currently
utilizing a number of gene-profiling technologies with
the aim of building up a comprehensive database of the many
different types of human tumor cell lines treated with the
Ras inhibitor FTS, either alone or in combination with other
drugs.We expect this database will be useful in following up
the current clinical trials with FTS, and will allow the future
design of trials with rational drug combinations.