Dasatinib, an oral inhibitor worth keeping an eye on?

TenderIsOurMight

Dasatinib, an oral inhibitor worth keeping an eye on?

TenderIsOurMight

Dasatinib is an oral "small molecule inhibitor", a relatively new group of drugs active at a molecular level in our body. Dasatinib inhibits a common pathway called the tyrosine kinase pathway and by so doing may block pathways essential for tumor growth.  It differs from Bavacizamub, a "monoclonal antibody" inhibitor of VEGF pathway (vascular endothelial growth factor) now in several promising phase 3 clinical trials which you may have already heard of.

Today I noticed Dasatinib is sponsored in a new NCI clinical trial designed to study it's effects in two differing doses on newly diagnosed stage IV breast cancer metastatic to bone.

Coincidentally, I came across the just published abstract below about Dasatinib's particular effectiveness in vitro on basal breast cancer cells, felt commonly represented in triple negative tumors.

Should you have a triple negative diagnosis, perhaps Dasatinib may well be worth your considered eye, along with that of your oncologists.

All the best to each of you,

Tender

I. Abstract: "Breast Cancer Res Treat. 2007 Nov;105(3):319-26. Epub 2007 

Dasatinib, an orally active small molecule inhibitor of both the src and abl kinases, selectively inhibits growth of basal-type/"triple-negative" breast cancer cell lines growing in vitro.

Finn RS, Dering J, Ginther C, Wilson CA, Glaspy P, Tchekmedyian N, Slamon Department of Medicine Division of Hematology, Oncology Geffen School of Medicine at UCLA, 10833 Le Conte Ave, 11-934 Factor Bldg, Los Angeles, CA, 90095, USA, rfinn@mednet.ucla.edu.

"Dasatinib is an orally active small molecule kinase inhibitor of both the src and abl proteins. To evaluate the potential role of dasatinib in breast cancer we used 39 human breast cancer cell lines that have been molecular profiled using Agilent Microarrays. They represent both luminal and basal breast cancer subtypes based on the relative gene expression of cytokeratin (CK) 8/CK18 and CK5/CK17, respectively, and those that have undergone an epithelial-to-mesenchymal transition (post-EMT) based on their expression of vimentin and the loss of CKs. When treated with 1 muM dasatinib in vitro 8 of them were highly sensitive (>60% growth inhibition), 10 of them were moderately sensitive (40-59% growth inhibition), and 21 were resistant to dasatinib. A highly significant relationship between breast cancer subtype and sensitivity to dasatinib was observed (chi (2) = 9.66 and P = 0.008). Specifically, basal-type and post-EMT breast cancer cell lines were most sensitive to growth inhibition by dasatinib. In an attempt to identify potential predictive markers of dasatinib response other than breast cancer subtype we analyzed the baseline gene expression profiles for differentially expressed genes. We identified a set of three biologically relevant genes whose elevated expression is associated with dasatinib inhibition including moesin, caveolin-1, and yes-associated protein-1 with a sensitivity and specificity of 88 and 86%, respectively. Importantly, these data provide scientific rationale for the clinical development of dasatinib in the treatment of women with "triple-negative" breast cancer, a subtype that is categorized as being aggressive and lacking effective treatments (i.e. hormonal manipulation or trastuzumab).

II. NCI Clinical Trial : Dasatinib in Treating Patients With Stage IV Breast Cancer That Has Spread to the Bone

This study is currently recruiting participants.
Verified by National Cancer Institute (NCI), November 2007

Sponsors and Collaborators:    Southwest Oncology Group
National Cancer Institute (NCI)
Information provided by:    National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:    NCT00410813
 
RATIONALE: Dasatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PURPOSE: This randomized phase II trial is studying two different schedules of dasatinib to compare how well they work in treating patients with stage IV breast cancer that has spread to the bone.

Breast Cancer
Metastatic Cancer
Drug: dasatinib
Procedure: diagnostic procedure
Procedure: laboratory biomarker analysis
Procedure: protein tyrosine kinase inhibitor therapy

http://clinicaltrials.gov   NCT00410813

Negative3Grade3

Thank you very much for sending us some valuable information, TenderIsOurMight.  Although I'm not eligible for the trial, I'd be following the progress they make.

badboob67

Tender,

Does this mean it is only effective for triple neg, or just more effective? Being stage IV bone mets only, the trial sounds interesting.

Thanks,

Diane 

TenderIsOurMight

Dasatinibs' effectiveness is clinically under active study, so really those answers are currently unknown.

I posted this thread so as to alert triple negative women to new research with small molecule therapy, and coincidentally read Dr. Finn's (UCLA) in vitro (in lab) research suggesting effect on triple negative cell type (basal).

Here is a link to MD Anderson's recruiting triple negative trial on this drug:

http://utm-ext01a.mdacc.tmc.edu/dept/prot/clinicaltrialswp.nsf/Index/2006-0988

Phase II Study of Dasatinib (BMS-354825) for Advanced 'Triple-negative' Breast Cancer</;</p> Tender

FloridaLady

Hi Tender,

This is the drugs I was telling you about.  It was originally called Gleevic and they made some changes and renamed.  This is the drug that was made for Leukemia patients.  This is the one you should have the c-kit receptor for it to really work.  MD Anderson has trial for this with the use of carboplatinum and taxotere.  They started last summer while I was there. 

I love it... one doctor says it's a harmless drug to use and the next said it still acts like a chemo just not as bad.  The worst thing is low blood counts and other chemo like symptoms  are milder.

This is my next line of treatment in December if I still have bc.  I don't want to travel to Houston again.  So my local doctor got approved to do this outside of a main trial.  I can not take it with another chemo because of my neuropathy is so bad.

Hopefully I will not need it.

Fla Lady

TenderIsOurMight

Fla Lady,



You're a model for always being prepared, always knowing you're next step. You simply amaze me! I believe this attitude has done you very well (although I'm saddened by your significant side effects).



Yes, I read the actual research paper today on the triple negative cells tested wit the Dasatinib in the lab, which correlated with their growth being inhibited. This is now the second paper validating this (Clark et al, 2005 also did), verifying the preclinical knowledge to allow clinical trials.



You taught me something today. I didn't know it was a retuned form of Gleevic.



Glad you have your local oncologist, and that you're doing well. You deserve it.



tender

Renairis

Hi Tender

Could this treatment be suitable, to your knowledge, for IDC, triple negative? I've had carboplatin taxol and avastin for mets.The combo helped but I think I've got another recurrence according to my last PET.Thank you for your invaluable information.

Rena

TenderIsOurMight

Hi Rena,



If you qualify under the clinical trial, it is indeed being studied in triple negative metastatic disease.



Here is the link to the MD Anderson trials:



1.Primary:http://utm-ext01a.mdacc.tmc.edu/dept/prot/clinicaltrialswp.nsf/Index/2006-0988

Study Summary Number: 2006-0988

To estimate objective response rate (ORR) of dasatinib in women with recurrent or progressive locally-advanced or metastatic 'triple-negative' breast cancer.



2. http://utm-ext01a.mdacc.tmc.edu/dept/prot/clinicaltrialswp.nsf/Index/2006-0900

Study Number: 2006-0900

Study Title:Phase I/II Study of Dasatinib in Combination with Zoledronic Acid for the Treatment of Breast Cancer Bone Metastasis



3. Here is the link to a Memorial Sloan Kettering trial:



Well, on review this morning MSK is indeed running a clinical trial that features a tyrosine kinase inhibitor similar to Dasatinib, but not specifically Dasatinib. So, as my thread is entitled Dasatinib, I won't confuse things by posting specifics. These drugs all have different numbers/names assigned.

But you can look at it here:

http://www.mskcc.org/mskcc/html/2270.cfm?IRBNO=07-112



Please know I am a patient just as yourself, always looking. I just wish to shed light as to what may be new and helpful for you kind ladies and men with triple negative disease.



All the best to you,

Tender