Tarceva

Isvit possible to take tarceva if you have brain mets as well as lung tumour

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It is, but Tarceva doesn't treat brain mets. Did you have radiation on the brain mets?
Take care, Judy

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Cathy

Tarceva is not typically thought of as a brain mets drug. However, a few brain diseases consistently respond to lipid-soluble small molecules. This is called systemic brain chemotherapy and it can also treat coexistent systemic disease in the rest of the body. Drugs like Temodar, Iressa and Tarceva are small molecule. Empirically, it has been shown to cross the blood-brain barrier (BBB) to affect cell death in circulating tumor cells (Cancer. 2006 Dec 5; JTO: November 2009 - Volume 4 - Issue 11 - pp 1415-1419 & JCO, Vol 24, No 27 [September 20], 2006: pp. 4517-4520). And results have come from studies of "multitargeted" tyrosine kinase inhibitors, small molecules that act on multiple receptors in the cancerous cells like Tykerb and Sutent.

Tarceva is a tyrosine kinase inhibitor. It also has an anti-angiogenic effect on cancer cells. There are a number of classes of drugs that target angiogenesis (VEGF). At the protein level is Avastin. At the tyrosine kinase level is Iressa, Nexavar, Sutent and Tarceva. At the intracellular metabolic pathway mTOR level is Afinitor and Torisel. The AngioRx Assay has identified potential responders to Avastin, Nexavar, Sutent and other anti-angiogenic drugs and assessed previously unanticipated direct and potentiating anti-angiogenic effects of targeted therapy drugs such as Tarceva and Iressa.

http://cancerfocus.org/forum/showthread.php?t=3738

Greg

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Yes in had 10 wbrt treatments in have a new mri on Aug 29. So keeping fingers crossed theyve shrunk then maybe get gamma knife, any other suggestions

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Are you a neuro dr, just wondered why you know so much about this thanks

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Keep in mind that even though some of the Tarceva can penetrate into the brain, it isn't necessarily enough to treat brain mets. There are some techniques such as high pulsed dosing (given 4x but only onces every 4 days, or a big dose once a week) to try to get more drug into the brain without being too toxic, but it's somewhat experimental still. I don't think many oncologists would rely on Tarceva alone, at least not for long.

Best hopes,

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Cathy

I do not have a prefix to my name. I am retired. Click on my moniker (gpawelski) and read my profile page.

The more Tarceva is "sensitive" (active) to your individual cancer cells, the more likely it will permeate the blood-brain barrier (BBB), without having to rely on pulse dosing. Pulsing with Tamoxifen can enhance the effectiveness of Tarceva.

http://cancerfocus.org/forum/showthread.php?t=3500

Newer approaches to treatment that combine anti-angiogenesis drugs with chemotherapy, other targeted drugs, or radiation may work better than using them alone. For instance, early studies that tested the drug Avastin by itself did not find it helped patients with cancer to live longer. But later studies found that when it was combined with chemotherapy to treat certain cancers, it helped some subsets of patients live longer than if they received the chemotherapy alone. The same is true with the anti-angiogenesis effects of Tarceva.

Greg

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No not a de just reading lots

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Greg,

I don't remember any studies saying that a cancer's sensitivity (e.g., in the lungs) to Tarceva predicts the amount of Tarceva that penetrates into the brain. Did I miss some research or did you mean that the more sensitive to Tarceva the cancer cells are, less Tarceva would be needed in the brain to be effective there?

Best hopes,

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The more "sensitive" cancer cells are to Tarceva, the better the permeation of the blood-brain barrier. Tarceva is after all, a small molecule drug that has the ability to dissolve through the capillary cell membranes and absorbed into the brain.

The intrinsic properties of malignancies themselves, rather than the qualities of individual drugs, are primarily responsible for their sensitivity with chemotherapy. Sensitivity of these malignancies result from an intrinsic 'locked-in' state to pro-apoptotic (cell death) stresses in these cells.

Even though cancer cells in some subsets of individuals, may be resistant to Tarceva, a drug like Tamoxifen can enhance the effectiveness of Tarceva. High-dose Tamoxifen can significantly inhibit the P-glycoprotein (gatekeeper in the blood-brain barrier) multidrug resistant membrane pump, as well as inhibit protein kinase C (preventing the increase in vascular resistance).

Greg

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Greg,

Can you offer a research citation for that? It doesn't makes sense to me that sensitivity of cancer cells in the *lung* to Tarceva makes the blood brain barrier any more permeable to Tarceva's small molecules than in say, Tarceva-resistant T790M-variant EGFR-driven cancer cells.

Best hopes,

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Tarceva is a small molecule drug that has the ability to dissolve through the capillary membranes and absorbed into the brain. So the more sensitive cancer cells are to Tarceva, the better the permeation effects to the blood-brain barrier. Citations are in the url address above.

Greg

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Greg,

I'm sorry but I cannot find any citation in that showing BBB permeability is correlated with Tarceva response by cancer cells in the lungs. It's obvious that permeability to small molecules would allow more Tarceva into the brain and that would increase the chance that Tareva might have an effect there if enough of the drug penetrates and the cancer is sensitive. But I would not expect that permeability of the BBB would change due to the particular EGFR molecular rearrangement in the independent cancer cells in a different organ. So if you can find the citation that says that and paste it right here it would be most helpful.

Best hopes,

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Hi All
The brain mets are lung cancer brain mets; so in effect we're talking about lung cancer of the brain, and if the cancer cells in the lung are sensitive to Tarceva then that will also be the case with the brain metastases. But the question of BBB's permeability is a different matter altogether, isn't it? I don't know.

Regards, Howard

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http://cancerfocus.org/forum/showthread.php?t=3500

All three drugs (Temodar, Iressa, Tarceva) are small molecule drugs (as opposed to being large molecule drugs) that can be used against brain metastases. Empirically (via previous randomized clinical trials), they have been shown to cross the blood-brain barrier (BBB) to kill circulating tumor cells (Cancer. 2006 Dec 5; JTO: November 2009 - Volume 4 - Issue 11 - pp 1415-1419 & JCO, Vol 24, No 27 (September 20), 2006: pp. 4517-4520).

And it isn't due to the particular EGFR molecular rearrangement stuff (the structural alteration of a chromosome that causes a change in the order of its loci). It's not just that it's a small molecule but, more importantly, because it's a lipid soluble molecule (better at crossing the blood brain barrier).

Greg

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Greg,

If that is what you were referring to, then it is not the cancer cells' sensitivity to Tarceva that causes the permeability of the BBB afterall, right? It sounds like your statement "The more Tarceva is 'sensitive' (active) to your individual cancer cells, the more likely it will permeate the blood-brain barrier (BBB), . . . " might have been miscommunicated. You just meant Tarceva is a small molecule drug so some of it can penetrate into the brain; it's ability to have an affect on the cancer is independent of the penetration.

I thought I remember reading elsewhere, though, that only a portion of the drug penetrates the BBB, hence the experimental use of high-dose pulsing to try to get more to cross at least periodically without exceeding a patients tolerance of side-effects.

Best hopes,

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Craig

I see what you're driving at. You are thinking about the T790M mutation, which has been thought to cause resistance by sterically blocking binding of Tarceva (Tarceva-resistant T790M-variant EGFR-driven cancer cells) in *lung* cancer cells. However, drug resistance evolves by multiple mechanisms. While some recurrent tumors have the secondary mutation in the EGFR kinase domain (T790M) conferring drug resistance, in other cases the mechanism underlying acquire resistance is unknown. T790M is only detected in a very small percentage of tumor cells.

The fact is that Tarceva is a lipid soluble small molecule, which makes it "better" at crossing the blood-brain barrier. The fact is that Tarceva inhibits the P-glycoprotein multidrug resistant membrane pump (the gatekeeper in the blood-brain barrier), so the more "sensitive" cancer cells are to Tarceva the better the permeation effect to the blood-brain barrier. And high-dose Tamoxifen can "significantly" help to to fight resistance mechanisms. There would be a huge advantage to the patient to receive a "sensitive" (active) drug, compared to a "resistant" (inactive) drug.

Greg

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Greg,

Yes, you're getting closer to what I was driving at. In your terms, I was driving at the assumption that
(A) "The fact is that Tarceva inhibits the P-glycoprotein multidrug resistant membrane pump (the gatekeeper in the blood-brain barrier)," means (B) "the more "sensitive" cancer cells are to Tarceva the better the permeation effect to the blood-brain barrier."

I'm having trouble believing (A) makes (B) a logical conclusion, and I didn't think that (A) was the primary mechanism of Tarceva resistance in EGFR-driven cancer except indirectly by allowing a higher dose get into the brain, so if it's not the primary mechanism or a major mechanism then (B) can't be assumed.

The primary mechanism of resistance to Tarceva are variants like T790M (early reports suggested it account for nearly half) and then there's other resistant variants of the mutations, different mutations (e.g., KRAS, BRAF), MET amplification, co-incident PIK3CA or an interited BIM gene, some kind of influence from FGFR or PDGFR. I think I even heard about a conversion to SCLC but I'm not sure of that. But I'm not aware of any research suggesting mebrane pumps are important in the mechanisms of resistance for Tarceva, although there's certainly a big wedge of the pie of "still unknown" that might include some form of that that for some % of resistance.

Best hopes,

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The discovery of ABC transporters (superfamily of carrier proteins) was recognized as the basis for the human P-glycoprotein drug resistance mechanisms. The over expression of P-glycoprotein involved in cellular transport is a frequent cause of multiple drug resistance. A genetic predisposition causes multiple proteins to dot the surface of tumor cells. These proteins are known as P-glycoprotein (PGP). PGP is a transmembrane efflux pump. It pumps harmful things from the inside of the cell to the outside of the cell. As soon as drugs enter the cancer cells, the PGP pumps start pumping the drugs out.

The presence of P-glycoprotein signals that the patients would not respond well to chemotherapy. PGP is primarily responsible for inducing multi-drug resistance, in which the tumors become resistant to many chemotherapy drugs. PGP effectively pumps the drug out of tumor cells before it has time to kill the cells. Harpole et al, found that patients with PGP survived 20.9 months on average, while patients without PGP had an average survival of more than 5 years after diagnosis.

Greg

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But Greg, as far as I can see from the research, P-glycoprotein drug resistance mechanisms have not yet been shown to be a significant cause of resistance to drugs like Tarceva. It is quite possible that someday it will be found to contribute to a type of resistance, but right now that's not what the research has shown and it doesn't seem be the primary cause.

Best hopes,

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Craig.

Research by Giovanna Ames, Piet Borst, Peter Wielinga, Michael Dean, et al and others, has recognized ABC (ATP-Binding Cassette) genes that represent the largest family of transmembrane proteins (transporters) as the basis for P-glycoprotein drug resistance mechanisms. The over expression of P-glycoprotein (PGP) involved in cellular transport is a frequent cause of multiple drug resistance. In many cases, PGP is responsible for a patient's decreased sensitivity to anti-cancer drugs. As soon as the drug enters the cancer cells, the PGP pumps start pumping the drug out. PGP effectively pumps the drug out of tumor cells before it has time to kill the cells. Tarceva is not exported by the PGP and other ABC transporters placed at the luminal membrane of brain capillaries. Thus the higher concentration of Tarceva in the central nervous system (CNS).

Greg

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