Monoclonal antibodies- Avastin @ Erbitux

• By gpawelski
• Posted October 23, 2009 at 1:10 pm
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The FDA has been seeking to broaden the range of use for cancer drugs. When they approve a drug for sale, they limit how drug makers sell it. A drug approved to treat only breast cancer cannot be marketed for lung cancer even if some studies suggest that the medicine may save some lung cancer patients.

But the FDA has proposed new guidelines that would change all this. The new rules would allow drug makers to provide physicians with copies of medical journal articles that discuss product uses that have not been vetted or approved by the FDA. Drug companies do not have to promise to adequately test the unapproved use discussed in the article.

Physicians are not overseen by the FDA. Medicine is regulated by state medical boards which let them prescribe drugs as they see fit regardless of FDA judgements. Physicians can prescribe drugs for unapproved uses. If the FDA doesn't end up approving Erbitux for lung cancer, it'll end up being used "off-label" for lung cancer anyway. It may end up finally being approved the way Avastin was finally approved for breast cancer.

Erbitux is a monoclonal antibody just like Avastin, but directed at a different protein. In addition to VEGF, researchers have identified a dozen other activators of angiogenesis, some of which are similar to VEGF. Erbitux binds to EGFR, a protein on the surface of a cell. It targets EGFR protein-tyrosine kinases.

But all the EGFR mutation or amplification studies can tell us is whether or not the cells are potentially susceptible to this mechanism (pathway) of attack. It doesn't tell you if Erbitux is better or worse than another drug which may target this. There are differences.

The drugs have to get inside the cells in order to target anything. In different tumors, either Erbitux or another drug might get in better or worse than the other. And the drugs may also be inactivated at different rates, also contributing to sensitivity versus resistance. Remember, why do some lung cancers stop responding to Tarceva? Why go through so much "trial-and-error?"

EGF-targeted drugs are poorly-predicted by measuring the ostensible target EGFR, but can be well-predicted by measuring the effect of the drug on the "function" of live cells. Without "individualized" testing, it's difficult to determine which drugs are best for patients.

More and more physicians and patients are turning to individualized therapies to treat cancers. Under this approach, scientists study how an individual's cancerous cells respond to several drugs. Doctors have learned that even when the disease is the same type, different patients' tumors respond differently to chemotherapeutic drugs. Without individualized testing, it's difficult to determine which drugs are best for patients.

There are numerous different therapeutic drug regimens out there. Any one or combination of them can help cancer patients. The system is overloaded with drugs and under loaded with wisdom and expertise for using them. What's needed is to make extensive use of bio-marker tests in treatment decisions.

The cell culture methodology maintains cancer cells in their native state, making cell-based assays of chemo compounds more reliable. The test relies on cells, rather than genetic tests, because the complexities and redundancies of human biology are beyond the ken of genomics.

Cancer is a complex disease and needs to be attacked on many fronts. The best thing to do is to combine these different tests in ways which make the most sense. The future of cancer therapy will be personalized treatments for individual patients, and will require a combination of novel diagnostics and therapeutics.

Improving cancer patient diagnosis and treatment through a combination of cellular and gene-based testing will offer predictive insight into the nature of an individual's particular cancer and enable oncologists to prescribe personalized treatment more in keeping with the heterogeneity of the disease. The biologies are very different and the response to given drugs is very different.

Literature Citation: Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 17117

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• By ACS
• Posted October 23, 2009 at 5:03 pm
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Thanks, great reply. I have had individualised testing on live cells done in Germany so I have and idea what may or may not work effectively.
The problem I now have is finding an oncologist in Australia prepared to work with this new data and not offer standardised chemo protocols.
Many thanks for your excellent feedback. No doubt individualised testing is the only sane way for future treatments.

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• By WRB123
• Posted October 23, 2009 at 6:26 pm
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My 67 year old husband has Stage III lung cancer. Is in a trial using Erbitux combined with Taxol and Carbo, high dose radiation. We have finished radiation and chemo and will have scan next week, results to follow on 11/2.

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• By gpawelski
• Posted October 23, 2009 at 10:55 pm
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ACS

The University of Sydney does research on cell-based assays. Perhaps they have oncologists at particpating hospitals that would be receptive to your data and offer treatment accordingly?

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• By ACS
• Posted October 24, 2009 at 4:31 am
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Thanks - you don't have a contact number for the Sydney Uni research do you?

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• By Richelle13
• Posted October 24, 2009 at 7:06 am
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Hi, my mum is seeing Dr Nick Pavlakis at the Royal North Shore Hospital in Sydney. not sure if he is involved in anything that you are after. There is also the Peter Mac Hospital in Melbourne that does a lot of clinical trials. don't think Avastin is on the PBS for lung cancer at this stage.

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• By Leilani
• Posted October 25, 2009 at 12:54 am
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Aloha Art,

I started this year with Avastin/Carboplatin/Taxol
for 3 months, then down to Avastin/Carboplatin for 3 months, now 4 months just Avastin.
I was diagnoised in April 2005 with stage 4 NSCLC,
and have been through 3 other combination of chemos along the way. Surgery was not available being my tumor is not operable. My tumor has shrunk, but will never ever go away. But I'm here 4 years longer than my Doctor gave me.
The Avastin seems to be leveling my condition with no heavy side effects. I do the treatment every 3 weeks and just keep moving ahead, day by day.
So far. so good for me personally.
I sure wish you the best.

Aloha Nui,
Leilani

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• By ACS
• Posted October 25, 2009 at 3:06 am
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Thanks Leilani @ Richelle,

A lot of people in Europe and the US are reporting good results with monoclonal antibodies like Avastin, not always in combination with chemotherapy protocols.
Plenty of research going on in Australia and big developments coming in years ahead, I'm told.
Certainly, treatment based on individualised testing and monolclonal antibodies are the big areas of research.

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• By gpawelski
• Posted October 25, 2009 at 8:54 am
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ACS

Targets for the new "smart" drugs can be located on the outside or inside of a cancer cell. The most common targets on the outside of a cancer cell are receptors, which are proteins that help relay chemical messages. Many targets on the inside of a cell are enzymes, which are proteins that help speed up chemical reactions in the body.

Monoclonal antibodies are "large" molecules. These very large molecules don't have a convenient way of getting access to the large majority of cells. Plus, there is multicellular resistance, the drugs affecting only the cells on the outside may not kill these cells if they are in contact with cells on the inside which are protected from the drug. The cells may pass small molecules back and forth.

Avastin (bevacizumab) is a monoclonal antibody, a type of genetically engineered protein. Monoclonal antibodies are substances made in the laboratory that recognize and then attach to specific proteins on the outside of cancer cells. They may be used to stimulate the immune system to attack cancer cells or to deliver radiation, chemotherapy, or other biologic therapies more directly to a tumor.

Avastin directly binds to a protein in the body called vascular endothelial growth factor (VEGF), which spurs the growth of blood vessels. Angiogenesis is dependent on VEGF. Avastin directly binds to VEGF to directly inhibit angiogenesis (microvasculature regression). Within 24 hours of VEGF inhibition, endothelial cells have been shown to shrivel, retract, fragment and die by apoptosis. VEGF can cut off the supply of vessels that spring up to feed a tumor, but there is some uncertainty how Avastin works, or if it can get "inside" a cell.

Exciting results have come from studies of multitargeted "small" molecule drugs like Sutent that act on multiple receptors in the cancerous cells. There have been a continuous parade of new targeted small and large molecule therapies introduced into the market virtually blind.

However, certain pre-testing assays have allowed physicians "targeted" testing to decrease the number of nonresponders (people who do not benefit from a drug) to targeted but expensive therapies, and increase the number of responders (people who benefit from a drug).

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