6 replies to this topic

[scuba]

3776 Cycling Toward Leukemia Stem Cell Elimination Wtih a Selective Sonic Hedgehog Antagonist

http://ash.confex.co...Paper41624.html

Our findings suggest that selective Shh antagonism induces cycling of dormant human blast crisis LSC, rendering them susceptible to BCR-ABL inhibition, while sparing normal progenitors.  Implementation of novel LSC splice isoform detection platforms to assess efficacy of Shh inhibitor-mediated sensitization to molecularly targeted therapy may inform dormant cancer stem cell elimination strategies that ultimately avert relapse.

[tiouki]

Hi scuba, thanks for sharing this.

I guess next step is to target stem cells to eliminate residual disease. I am quite confident that new approaches, impacting cell cycle regulating proteins, will lead to new treatments

Fingers crossed

Pierre

EDIT :

a scientific review on leukemic stem cells, the text is free if anyone is interested :http://www.impactjou...=333&path[]=551

Some figures like table 2 are interesting as a summary of these approaches and potential targets

The last words of the authors :

Theoretically, to eradicate a leukemic process, it is mandatory to eliminate the last leukemic stem cell; this might be the definitive objective in CML [119]. Nowadays, many signaling pathways involved in hematopoietic stem cell maintenance have been described, and a few inhibitors (some in clinical use) have been identified. It is then possible to affect more or less specifically LSCs. The option of targeting CML stem cells in patients in sustained UMRD [=PCRU] must be considered with precaution because of the probable side effects of the drugs. In this circumstance, a prior evaluation of the LSC compartment could be useful.

EDIT 2 :

another article about Sonic hedgehog pathway (abstract only), which seems quite promising indeed :

http://www.ncbi.nlm....pubmed/21660044

[CallMeLucky]

Found these on another user forum.  These are various Hedgehog drugs in development.  Some are currently in combination clinical trial with TKI drugs.

IPI-926 (generic assigned name Saridegib) - Infinity Pharmaceuticals

GDC-0449 (generic name approved Vismodegib) - Genentech

LDE-225 - Novartis Oncology

XL-139 (aka BMS-833923) - BMS/Exelixis

PF-04449913 - Pfizer

TAK-441  - Millennium Pharmaceuticals

[tiouki]

Thank you callmelucky, I'll check this out.

Apparently for BMS-833923 there are some phase II clinical trials dasatinib vs dasatinib + BMS-833923, if anyone has some information about it or is enrolled in it that would be nice !

http://www.cancer.go...earchid=6580284

Here they are trying a vaccine !

Phase I

http://www.cancer.go...earchid=6406535

Phase II

http://www.cancer.go...earchid=6406535

Same question has anyone tried it?

I am looking forward to see the results !!

[CallMeLucky]

That phase I trial is a bit tricky.  Phase I is usually patients that are not doing well and the trade off of trying something experimental is offset by the prognosis.  CP-CML patients on Imatinib have a very good prognosis.  It is very brave (risky) to participate in Phase I trial when you have a good prognosis.  Very interesting the only trial site is in Iran.

Also interesting is the fact that they are only targeting b3a2 breakpoint.  Since most people with CML have b2a2, I am speculating that even if the vaccine controls the b3a2, this might not result in a cure if it doesn't control b2a2.  Still a good start, especially if b3a2 is driving any resistance.

I also noted that all of these Hedgehog trials talk about enhancing the TKI for resistant patients, none of them set a goal of eliminating LSC.  However, MDAC has on their site a write up on Hedgehog inhibitors.  It is included in a section under TKI failure, but in addition to treating resistant forms of CML, they also explicitly state they are looking to do trials with Hedgehog inhibitors to try and cure people with CML http://www.mdanderso...ki-failure.html

[scuba]

[Pin]