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Old 12-29-2007, 11:07 PM   #1
Lani
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Join Date: Mar 2006
Posts: 4,772
Happy New Year--a new and promising oral drug which crosses the blood brain barrier

and targets multiple members of the her family is being developed with promising results:

Mol Pharmacol. 2007 Nov 1 [Epub ahead of print] Links
Cellular and in vivo activity of JNJ-28871063: a non-quinazoline pan-ErbB kinase inhibitor that crosses the blood brain barrier and displays efficacy against intracranial tumors.

Emanuel SL, Hughes TV, Adams M, Rugg CA, Fuentes-Pesquera A, Connolly PJ, Pandey N, Moreno-Mazza S, Butler J, Borowski V, Middleton SA, Gruninger RH, Story JR, Napier C, Hollister B, Greenberger LM.
Bristol-Myers Squibb.
JNJ-28871063 is a potent and highly selective pan-ErbB kinase inhibitor from a novel aminopyrimidine oxime structural class that blocks the proliferation of epidermal growth factor receptor (EGFR; ErbB1) and ErbB2 overexpressing cells but does not affect the growth of non-ErbB overexpressing cells. Treatment of human cancer cells with JNJ-28871063 inhibited phosphorylation of functionally important tyrosine residues in both EGFR and ErbB2 and blocked downstream signal transduction pathways responsible for proliferation and survival. A single dose of compound reduced phosphorylation of ErbB2 receptors in tumor bearing mice, demonstrating target suppression in vivo. Tissue distribution studies show that JNJ-28871063 crosses the blood brain barrier and penetrates into tumors where it is able to accumulate to higher levels than those found in the plasma. JNJ-28871063 showed oral antitumor activity in human tumor xenograft models that overexpress EGFR and ErbB2. In an intracranial ErbB2 overexpressing tumor model, JNJ-28871063 extended survival relative to untreated animals. The brain is a primary site of metastasis for EGFR overexpressing lung cancers and ErbB2 overexpressing breast cancers. Therefore, the ability to penetrate into the brain could be an advantage over existing therapies such as trastuzumab (Herceptin) and cetuximab (Erbitux), which are antibodies and do not cross the blood brain barrier. These results show that JNJ-28871063 is orally bioavailable, has activity against EGFR and ErbB2-dependent tumor xenografts, and can penetrate into the brain and inhibit ErbB2 overexpressing tumor growth.
PMID: 17975007 [PubMed - as supplied by publisher]
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Old 12-29-2007, 11:10 PM   #2
Lani
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a simpler review of the paper, more readable

Mol Pharmacol. 2007 Nov 2 [Epub ahead of print] Links
Revoking the Privilege: Targeting HER2 in the CNS (Relates to article by Emanuel, et al., Fast Forward 1 Nov 07).

Contessa JN, Hamstra DA.
The University of Michigan.
Pharmacologic agents developed for cancer therapy have traditionally relied on a therapeutic ratio of effects between tumors and normal tissue. Over the past decade this concept has been refined through the development of agents that are intended to specifically target tumor cells. The EGFR (ErbB) family of receptor tyrosine kinases is an intensely studied target in many cancer cell types and several successful therapeutic agents have been developed to block the growth promoting functions of these receptors. However, with their success has come the evolution of novel clinical scenarios by which tumor cells can evade specific therapies. Trastuzumab, a monoclonal antibody to Her2/ErbB2 that is utilized in breast cancer, has been shown to provide a survival benefit for patients whose tumors express this receptor, but does not have activity in the central nervous system due to the blood brain barrier. Efforts to improve current strategies of targeting this receptor may lead not only to benefits in the treatment of breast cancer but also to advances in the treatment of other CNS malignancies such as gliomas and medulloblastoma.
PMID: 17981994 [PubMed - as supplied by publisher]

Both papers are available in full to all who Google "entrez pubmed" and type the PMID number into the rectangle (not really geak-speak, but best I can do at the moment!)

Great addition to the her2+ breast cancer warrior armory!
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Old 12-30-2007, 02:32 AM   #3
kat in the delta
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Posts: 224
Smile kat in the Delta

Thanks Lani for the info... I will have go back and read it again with my chemobrain... Do you think that chemobrain is from lack of circulation... or do some of the other drugs also penetrate the brain... in a bad way to me....
I will reread the article you posted... Thanks again for all your help.. We need it !! Let me know if you find out anything about chemobrain..
Kat in the delta

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Old 12-30-2007, 05:56 PM   #4
fullofbeans
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Join Date: Jan 2007
Location: UK
Posts: 617
Many thanks for info.

I am unclear Perhaps I am wrong these are kinase inhibitors so like other already available they do cross the brain blood barrier so what is new there? [ except off course that I always like to hear about new treatments in the pipeline, more armory indeed)


I am looking forward to see a publication that insist testing blocking all Her pathways!
__________________

35 y/o
June 06: BC stage I
Grade 3; ER/PR neg
Her-2+++; lumpectomies

Aug 06: Stage IV
liver mets: 6 tumours
July 06 to Jan 07: 2*FEC+6*Taxotere; 3*TACE; LITT
March 07- Sept 07: Vaccination trial (phase 2, peptide based) at the UW (Seattle).
Herceptin since 2006
NED til Oct 09
Recurrence Oct 2009: to internal mammary gland since October 2009 missed on Oct and March 2010 scan.. palpable nodes in May 2010 when I realised..
Nov 2011:7 mets to lungs progressing fast failed hercp/tykerb/xeloda combo..

superior vena cava blocked: stent but face remains puffy

April 2012: Teresa Trial, randomised to TDM1
Nov 2012 progressing on TDM1
Dec 2012 blockage of my airways by tumours, obliteration of these blocking tumours breathing better but hoping for more- at mo too many tumours to count in the lungs and nodes.

Dec 2012 Starting new trial S-222611 phase 1b dual egfr her2+ inhibitor.



'Under no circumstances should you lose hope..' Dalai Lama
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Old 12-31-2007, 09:48 AM   #5
Lani
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Join Date: Mar 2006
Posts: 4,772
fullof beans

what is different is that this TKI is much more specific

Most TKIs are promiscuous (yes, that is the word I have learned to use by reading the articles and listening to conference talks!) in that they act not just on one kind of receptor's phosphorylation site, but that of any of a number of similar receptor's phyosphorylation site (to block their function)

Thus lapatinib may work on IGFR1 as well as EGFR and her2, some VEGF inhibitors may also work on PGFR.

The problem with that is that they can have unanticipated negative functions as well as beneficial functions, as these receptors are found on all sorts of cells and can have important functions necessary to those people taking them.

The second difference is that it blocks not just her1 and 2 like lapatinib, but her4 as well (her 3 has no functional intracellular phosphylation site and has to pair with her1,2,or 4 to "borrow" theirs) do this drug may essentially do the same as that article on "curing" mice with the 3 drug combo--herceptin, pertuzumab and iressa. And this drug is oral, not IV (pertuzumab is IV, iressa a pill). Since iressa is made by a different drug company than herceptin and pertuzumab I think it will be a long time before that combo is tested in a clinical trial, unless Genentech can substitute Tarceva for Iressa.

This is one drug made by one company (with a lot of money from Sales of baby powder and baby shampoo as long as our population keeps growing!)
THAT BRINGS HOPE trials will proceed faster than if they had to test a three drug combination, with only one of the drugs being FDA approved already.

So the answer to "what's the big deal" is ...it MAY turn out to be a big deal!

Happy New Year!
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Old 01-03-2008, 06:55 PM   #6
fullofbeans
Senior Member
 
Join Date: Jan 2007
Location: UK
Posts: 617
Thanks Lani for the further explanation very clear indeed. This does indeed sound like a big deal, great!

I whish drug could be developped faster.
__________________

35 y/o
June 06: BC stage I
Grade 3; ER/PR neg
Her-2+++; lumpectomies

Aug 06: Stage IV
liver mets: 6 tumours
July 06 to Jan 07: 2*FEC+6*Taxotere; 3*TACE; LITT
March 07- Sept 07: Vaccination trial (phase 2, peptide based) at the UW (Seattle).
Herceptin since 2006
NED til Oct 09
Recurrence Oct 2009: to internal mammary gland since October 2009 missed on Oct and March 2010 scan.. palpable nodes in May 2010 when I realised..
Nov 2011:7 mets to lungs progressing fast failed hercp/tykerb/xeloda combo..

superior vena cava blocked: stent but face remains puffy

April 2012: Teresa Trial, randomised to TDM1
Nov 2012 progressing on TDM1
Dec 2012 blockage of my airways by tumours, obliteration of these blocking tumours breathing better but hoping for more- at mo too many tumours to count in the lungs and nodes.

Dec 2012 Starting new trial S-222611 phase 1b dual egfr her2+ inhibitor.



'Under no circumstances should you lose hope..' Dalai Lama
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