Hedgehog in CML treatments

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3/31/2009 in Medscape Today:

" We show that Hedgehog signaling is activated in LSCs through upregulation of

Smo. While Smo(-/-) does not impact long-term reconstitution of regular

hematopoiesis, the development of retransplantable Bcr-Abl-positive leukemias

was abolished in the absence of Smo expression. Pharmacological Smo inhibition

reduced LSCs in vivo and enhanced time to relapse after end of treatment. Our

results indicate that Smo inhibition might be an effective treatment strategy to

reduce the LSC pool in CML.

" Patients who harbour a BCR–ABL1T315I point mutation are resistant to this drug

and other tyrosine kinase inhibitors. A report in Nature now identifies a

potential new therapeutic strategy for this disease. Tannishtha Reya and

colleagues have shown that inhibition of the hedgehog (Hh) signalling pathway

reduces the number of normal and malignant haematopoietic stem cells (HSCs) and

blocks CML propagation. "

More information located at CML Resource Center:

http://www.medscape.com/resource/cml

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Abstract (7-15-2008)

" Chronic myeloid leukemia (CML) has led the way for developing rational drug

development in cancer. Most cases of CML diagnosed and treated in chronic phase

are extremely well controlled with imatinib monotherapy, and primary resistance

is very uncommon. Even though the treatment failure rate is low, the emergence

of drug resistance and the lack of eradication of the hematopoietic stem cell

clone has prompted a wave of drugs to address one or both these problems.

Several clinical trials (Phase I and II) of dasatinib or nilotinib in the

treatment of imatinib-resistant or -intolerant Ph chromosome-positive leukemia

have already reported a remarkable rate of hematologic response greater than 90%

for chronic-phase patients. These drugs minimize the risk of acquired drug

resistance that is particularly seen within the first 24-36 months of therapy,

and can prevent early failure in these patients. "

http://www.medscape.com/viewarticle/576209

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Monitoring the Disease Responses & Measuring Minimal Residual Disease (Future

Oncology. 2008;4(3):359-377. © 2008 Future Medicine Ltd.)

" Even though routine cytogenetic analysis is still considered the gold standard

for evaluating response in CML, the studies are often somewhat cumbersome in

practice and require analysis in metaphase. As most patients are able to achieve

complete cytogenetic responses with tyrosine kinase inhibitors (TKIs), sensitive

and accurate monitoring of bcr-abl is required to measure residual disease. In

CML patients who achieved a complete cytogenetic response, fluorescence in situ

hybridization (FISH) is more sensitive than conventional cytogenetics to monitor

Ph negativity, and thus a biologic response to treatment.[17] Since FISH studies

typically involve looking for the bcr-abl fusion fluorescence in at least 200

interphase cells, this precludes the sensitivity of FISH in making judgments on

the extent of residual disease. Furthermore, since most CML studies have

assessed long-term outcomes by monitoring cytogenetics and not FISH,

quantitative RT-PCR (qRT-PCR) is currently used for assessing the depth of the

molecular response and measurement of residual disease with a sensitivity of up

to 10-8. Molecular remission can thus be defined in this fashion as a reduction

in the quantification of bcr-abl transcripts to an undetectable level, and can

be considered as a surrogate marker for cure and/or long-term disease control.

It has been shown that such precision might help to predict disease outcome in a

better way. Major molecular response is defined as a reduction of bcr-abl

transcript levels by 3 or more logs, compared with a standardized baseline,

obtained from newly diagnosed and untreated CML patients. "

http://www.medscape.com/viewarticle/576209_4

FYI,

Lottie Duthu