future one, two punch: velcade, then IPI-504?

[Guest guest]

Greeting,

This is a report on preclinical work, hence too early to be of use to

patients, but I think the finding illustrates a basic next-generation

approach to targeted therapy: identifying how the cells adapt to the

targeted drug and then designing a drug that targets the adaptation.

(Much like in boxing, the successful fighter notices that his opponent

always avoids the left jab by ducking, and so follows that with a right

uppercut. Sorry ladies, showing my macho side : ).

So in this report, the authors describe how MCL cells (implanted in a mouse)

adapt to bortezomib (Velcade, already proven to be active against MCL), and

how a new drug (IPI-504) that targets how the cell adapts to Velcade leads

to more efficiently killing of the tumor cells.

Any trials yet with this combination? Not yet, although there is one ALK

positive lymphoma study for IPI-504

http://clinicaltrials.gov/ct2/show/NCT01119495 so we might anticipate a

combination study, assuming the safety profile of IPI-504 is acceptable at

therapeutic doses.

Karl Schwartz

Patients Against Lymphoma

Website: www.lymphomation.org

Mission: www.lymphomation.org/mission.htm

==

Blood. 2010 Nov 24.

The Hsp90 inhibitor IPI-504 overcomes bortezomib [Velcade] resistance in

mantle cell lymphoma in vitro and in vivo by downregulation of the

prosurvival ER chaperone BiP/Grp78.

Roué G, Pérez-Galán P, Mozos A, López-Guerra M, Xargay-Torrent S, Rosich L,

Saborit-Villarroya I, Normant E, Campo E, Colomer D.

Hematopathology Unit, Department of Pathology, Hospital Clinic, Institut

d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), University of

Barcelona, Barcelona, Spain;

Abstract (technical)

Despite the promising introduction of the proteasome inhibitor bortezomib in

the treatment of mantle cell lymphoma (MCL), not all patients respond, and

resistance often appears after initial treatment.

By analyzing a set of 18 MCL samples, including cell lines with constitutive

or induced resistance to bortezomib, we found a high correlation between

loss of sensitivity to the proteasome inhibitor and up-regulation of the

prosurvival chaperone BiP/Grp78.

BiP/Grp78 stabilization was ensured at a post-transcriptional level by an

increase in the chaperoning activity of heat shock protein of 90 kDa

(Hsp90).

In bortezomib-resistant cells, both BiP/Grp78 knockdown and cell

pre-treatment with the Hsp90 inhibitor of the ansamycin class, IPI-504, led

to synergistic induction of apoptotic cell death when combined with

bortezomib.

Cell exposure to the IPI-504-bortezomib combination provoked the

dissociation of Hsp90/BiP complexes, leading to BiP/Grp78 depletion,

inhibition of unfolded protein response (UPR), and promotion of

NOXA-mediated mitochondrial depolarization.

The IPI-504-bortezomib combination also prevented BiP/Grp78 accumulation,

thereby promoting apoptosis and inhibiting the growth of

bortezomib-resistant tumors in a mouse model of MCL xenotransplant (tumor

implanted in mouse).

In summary, our results suggest that targeting UPR activation via the

inhibition of Hsp90 may be an attractive model for the design of a new

bortezomib-based combination therapy for MCL.