[cancercured] Aurora A kinase inhibitor

Greetings,

Much progress has been made towards understanding cancer cells - what
makes them different from normal cells of the same type, and how to
design drugs that bind to and disrupt these processes ... like a well
placed cog in a maligant wheel.

Gleevec demonstrated just how valuable a targeted drug can be;
transforming a dire cancer call MCL to one that's highly treatable
today.

We are now beginning to see hundreds of drug molecules designed in
this way based on growing insights into the "machinery" of cancer
cells. The molecular interactions that drive loss of growth controls
in malignant cells, which can vary a lot among cancer cell types.

Anyhow, below is some information on but one, and I have no clue if
it will be active or effective against lymphomas, or which type. This
drug target seems relevent to MCL according to the scraps copied
below.

When might a patient consider such an agent in the early phase of
clinical testing?

Just lay opinion, but probably phase I studies are appropriate only
when better-understood and effective therapies are not working and
the patient has little to lose in trying the investigational agent.
The hope being that the target it binds to is critical to the
malignant process. But achieving clinical benefit in a phase I study
is a long shot, particulary since the dose might not yet be optimal
or the effects may not be sufficient as a single agent. But at least
it would provide hope that is reasonable and based on science.

=
Aurora A kinase inhibitor MLN8237 A second-generation, orally
bioavailable, highly selective small molecule inhibitor of the
serine/threonine protein kinase Aurora A kinase with potential
antineoplastic (anti-cancer) activity.

Aurora kinase inhibitor MLN8237 binds to and inhibits Aurora A
kinase, which may result in disruption of the assembly of the mitotic
spindle apparatus, disruption of chromosome segregation, and
inhibition of cell proliferation. (cog in the wheel)

Aurora A kinase localizes to the spindle poles and to spindle
microtubules during mitosis, and is thought to regulate spindle
assembly. Aberrant expression of Aurora kinases occurs in a wide
variety of cancers (seems to have good specificity - target might be
unque to cancer cells and not normal cells)

=
Cancer Genetics

Analysis of Aurora-A and hMPS1 mitotic kinases in mantle cell lymphoma
http://www3.interscience.wiley.com/journal/110576813/abstract?
CRETRY=1&SRETRY=0

Aurora-A and hMPS1 are kinases involved in spindle checkpoint and
centrosome duplication regulation and whose alterations have been
associated with cell transformation and chromosome instability in
different tumor models.

In this study, we have examined the possible alterations of these
genes in 58 mantle cell lymphomas (MCLs) and 4 MCL-related cell
lines.

Aurora-A was also examined in 46 diffuse large B-cell lymphomas
(DLBCLs). Aurora-A and hMPS1 mRNA expression levels were related to
tumor proliferative activity.

Interestingly, a MCL case with the highest number or chromosomal
imbalances also showed an extremely high value of Aurora-A mRNA
expression. No Aurora-A gene amplifications were detected in any
tumor or cell line, whereas hemizygous hMPS1 gene deletions were
observed in 23% of MCLs and 3 of the 4 cell lines.

However, no expression alterations or gene mutations were detected in
these cases. The Aurora-A proposed cancer susceptibility polymorphic
variant (P31I) was observed with a similar frequency in MCL, DLBCL,
chronic lymphocytic leukemia and in the 431 healthy controls.

However, the 3 MCLs and 4 DLBCLs with the homozygous variant of this
polymorphism had particular clinical characteristics with an unusual
early-age presentation and second epithelial malignancies in MCL and
extranodal origin in DLBCL. These findings indicate that Aurora-A and
hMPS1 aberrations are uncommon in aggressive lymphomas but Aurora-A
overexpression may contribute to numerical chromosomal alterations in
occasional MCL. Although the Aurora-A P31I polymorphic variant is not
directly involved in a genetic predisposition to these lymphomas, it
may modulate the clinical presentation of these tumors.

Early clinical (phase I) testing:
http://clinicaltrials.gov/ct2/show/NCT00697346

--------------------
All the best,

Karl

Patients Against Lymphoma

www.Lymphomation.org

------------------------------------

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