What’s Wrong with Avastin?

Nothing really. It’s a wonderful drug that incorporates the brilliant insights originally articulated by Judah Folkman, MD, at Harvard University. Dr. Folkman reasoned that:

  1. Cancers require oxygen and nutrients
  2. These would need to be delivered by a blood supply
  3. Tumors would avidly seek their own blood supply via humoral factors.

His groundbreaking work ultimately lead to the discovery of VEGF, as well as the FDA approval of Avastin, the monoclonal antibody that binds and inactivates circulating VEGF in patients. The problem isn’t with Avastin, it’s with the practice of oncology – the clinical trial process and the muddied waters that surround clinical utility of any drug, new or old.

There are no perfect drugs. There are simply drugs that work for certain patients. VEGF down-regulation is an attractive and highly appropriate therapy for a subset of cancer patients with many different diagnoses whose tumors use the VEGF pathway to their advantage. Avastin combined with carboplatin and taxol has improved the survival of lung cancer patients. Avastin plus folfox has improved survival for colon cancer patients. Avastin plus chemotherapy improves the survival of some breast cancer patients. The problem is that it doesn’t improve the survival of all breast cancer patients.

When the FDA rules on the clinical utility of a drug, they use a broad-brush approach that looks at the global outcomes of all patients, determining whether these glacial trends reflect a true climate change. The problem is that while Bethesda, Maryland may not be noticing significant changes in ocean levels, people who live on the Maldives are having a very different experience. As these scientists ponder the significance of Avastin, some breast cancer patients are missing out on a treatment that could quite possibly save their lives.

One breast cancer patient’s life saving therapy is another’s pulmonary embolism without clinical benefit. Until such time as cancer patients are selected for therapies predicated upon their own unique biology, we will confront one Avastin after another. Our solution to this problem has been to investigate the VEGF targeting agents in each individual patient’s tissue culture, alone and in combination with other drugs, to gauge the likelihood that vascular targeting will favorably influence each patient’s outcome. Our results to date in patients with non-small cell lung cancer, colorectal cancer and even rare tumors (like medullary carcinoma of the thyroid) suggest this to be a highly productive direction for future development.

About Dr. Robert A. Nagourney
Dr. Nagourney received his undergraduate degree in chemistry from Boston University and his doctor of medicine at McGill University in Montreal, where he was a University Scholar. After a residency in internal medicine at the University of California, Irvine, he went on to complete fellowship training in medical oncology at Georgetown University, as well as in hematology at the Scripps Institute in La Jolla. During his fellowship at Georgetown University, Dr. Nagourney confronted aggressive malignancies for which the standard therapies remained mostly ineffective. No matter what he did, all of his patients died. While he found this “standard of care” to be unacceptable, it inspired him to return to the laboratory where he eventually developed “personalized cancer therapy.” In 1986, Dr. Nagourney, along with colleague Larry Weisenthal, MD, PhD, received a Phase I grant from a federally funded program and launched Oncotech, Inc. They began conducting experiments to prove that human tumors resistant to chemotherapeutics could be re-sensitized by pre-incubation with calcium channel blockers, glutathione depletors and protein kinase C inhibitors. The original research was a success. Oncotech grew with financial backing from investors who ultimately changed the direction of the company’s research. The changes proved untenable to Dr. Nagourney and in 1991, he left the company he co-founded. He then returned to the laboratory, and developed the Ex-vivo Analysis - Programmed Cell Death ® (EVA-PCD) test to identify the treatments that would induce programmed cell death, or “apoptosis.” He soon took a position as Director of Experimental Therapeutics at the Cancer Institute of Long Beach Memorial Medical Center. His primary research project during this time was chronic lymphocytic leukemia. He remained in this position until the basic research program funding was cut, at which time he founded Rational Therapeutics in 1995. It is here where the EVA-PCD test is used to identity the drug, combinations of drugs or targeted therapies that will kill a patient's tumor - thus providing patients with truly personalized cancer treatment plans. With the desire to change how cancer care is delivered, he became Medical Director of the Todd Cancer Institute at Long Beach Memorial in 2003. In 2008, he returned to Rational Therapeutics full time to rededicate his time and expertise to expand the research opportunities available through the laboratory. He is a frequently invited lecturer for numerous professional organizations and universities, and has served as a reviewer and on the editorial boards of several journals including Clinical Cancer Research, British Journal of Cancer, Gynecologic Oncology, Cancer Research and the Journal of Medicinal Food.

12 Responses to What’s Wrong with Avastin?

  1. Barbara Hiller says:

    Thanks for this post! I am one of the women with breast cancer who IS responding to Avastin. Had I stayed with my original oncologist, I would not be here to write this now. Thanks to chemosensitivity testing, I am. It’s crazy that, instead of approving chemosensitivity testing and using Avastin on the population for whom it will work, the FDA and Breast Cancer Action have come out against the drug itself.

  2. Very happy to learn of your good outcome. Every cancer patient is unique. Your individual benefit reflects the fortunate intersection of an active drug and a responsive tumor. The problem with the current clinical trial system (upon which drug approvals are based) is known as beta errors. Beta errors occur when benefit is “missed”. The subset of patients that benefit from any therapy (indeed many therapies) do not rise to statistical significance and as such cannot turn the ship-of-state fast or hard enough to change policy. The term is “outliers”. You, I am glad to say, are an outlier. Good luck for continued success. We as a laboratory exist to meet the needs of outliers like you.

  3. We are all biochemical individuals – this is clear from the landmark work of Drs Roger Williams and Robert Nagourney.

    Foolish consistency is the hobgoblin of little minds.

    Luckily we have men like Robert Nagourney to think outside the box. Keep up the great work!

    Non illigitamus carborundum – Don’t let the bastards wear you down.

  4. Linda Stacy says:

    Dr. Nagourney —
    Do you test for effectiveness of Avastin as part of your assays?

    Linda Stacy

    • We do. We test for avastin and several small molecules inhbitors of the VEGFr singling pathway. Over the years we have explored the activity profiles of a number of compounds with tyrosine kinase inhbition for the signal pathway associated with VEGF. While VEGF drugs are not often highly active as single agents in the clinic or in the laboratory, they clearly potentiate the effects of other drugs and have proven very useful in combination therapies.

  5. Annamaria Picollo says:

    Great article. One I will keep in mind in case my “good natured” early stage 1 with all the best prognostic characteristics decides to become aggressive.

    Since my small tumor is 90% estrogen, 40% progesteron Her2-, I am on Arimidex. Since Arimidex is a form of chemo , do you have the ability to test aromatase inhibitors to see if the drug will be effective in controlling a woman’s breast cancer tumor?

    I was never informed of the service you offer. Every woman needs to know whether the drug being recommended will work against her cancer. Chem is an experience one would not want to repeat due to a lack of knowledge.

    I found out about your service by reading a post on Breast Cancer.Org. An oncology nurse stated that everyone needs to educate themselves as to the best treatment plan for them. Your site was given for women to contact.
    Annamaria

    • Thank you for your comments. We are indeed fortunate to have the use of hormonal therapies that can provide benefit with comparitivley low toxicity and I agree whole heartedly with thier use in patients with node negative, ER positive tumors. Hormones are natural substances and they are aomong the most elegant targets for therapy. We do not test the aromatase inhibtors in our laboratory. Their mode of action is to decrease the synthesis of estradiol in the body tissues and as such do not give a measureable signal in our system. Good luck with you therapy. It sound very appropriate.

  6. Gregory D. Pawelski says:

    Clinical scientists involved with “real time” cell function analysis have found that Avastin as a “single agent” is relatively ineffective in virtually all tumor types other than Renal cancer. Beyond that, it appears to better deliver the effects of other classes of drugs.

    Some scientists are not sure whether Avastin or any other anti-angiogenic agents are working primarily by pruning new blood vessels, increasing the delivery of another anti-cancer therapy, or potentially another mechanism.

    Many patients are treated not only with a targeted therapy drug like Avastin, but with a combination of chemotherapy drugs. Therefore, existing DNA or RNA sequences or expression of individual pathways often examine only one compenent of a much larger, interactive process.

    The oncologist might need to administer several chemotherapy drugs at varying doses because tumor cells express survival factors with a wide degree of individual cell variability.

    Perhaps Genentech should use these assays to identify a potential target population of cancer patients that it thinks will benefit from the drug and then conduct a randomized clinical trial among this group.

  7. Pingback: Is Avastin Working for You? « Rational Therapeutics – Hope Practiced Here for Cancer Patients

  8. Pingback: Not Responding to the Standard Cancer Treatment? Maybe You’re an Outlier « Dr. Robert A. Nagourney's Blog

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