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The Future of Cancer Research Lies Behind Us


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The TED (Technology Entertainment Design) conferences have been held annually for almost two decades. It draws together innovators in a broad spectrum of disciplines. With invited speakers ranging from Harvard's Edward O. Wilson to business leaders like Microsoft's Bill Gates, the lectures cover a panoply of interesting topics.

Dr. Robert Nagourney was invited to present at the TEDxSoCal conference held in Long Beach, CA on July 16th. His interest was to engage this group in a discussion of cancer biology with the focus on biochemistry and metabolism. His lecture was timely in the context of the New York Times article on the failures of genomics platforms for cancer treatment.

Over the past year, there has been a growing recognition that genomic analyses are not providing the therapeutic insights that patients so desperately need. The Duke University lung cancer gene program, which received much attention, is emblematic of the hubris associated with contemporary genomic analytic platforms.

Dr. Nagourney has reviewed the contemporary experience in clinical trials, examined the potential pitfalls of gene-based analysis, and described the brilliant work conducted by biochemists and cell biologists, like Hans Krebs and Otto Warburg, who published their seminal observations decades before the discovery of the double helix structure of DNA.

He described insights gained using the cell-based funtional profiling analytic platform, that lead to treatments used today around the world, all of which were initially discovered using cell-based studies. More interesting still will be the opportunity to use these platforms to explore the next generation of cancer therapies – those treatments that influence the cell at its most fundamental level – its metabolism.



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In a conference sponsored by the Institute of Medicine, scientists representing both public and private institutions examined the obstacles that confront researchers in their efforts to develop effective combinations of targeted cancer agents.

In a periodical published by the American Society of Clinical Oncology (ASCO) in their September 1, 2011 issue of the ASCO Post, contributor Margo J. Fromer, who participated in the conference, wrote about it.

http://www.ascopost.com/articles/septem ... enges.aspx

One of the participants, Jane Perlmutter, PhD, of the Gemini Group, pointed out that advances in genomics have provided sophisticated target therapies, but noted, “cellular pathways contain redundancies that can be activated in response to inhibition of one or another pathway, thus promoting emergence of resistant cells and clinical relapse.”

James Doroshow, MD, deputy director for clinical and translational research at the NCI, said, “the mechanism of actions for a growing number of targeted agents that are available for trials, are not completely understood.”

He went on to say that the “lack of the right assays or imaging tools means inability to assess the target effect of many agents.” He added that “we need to investigate the molecular effects . . . in surrogate tissues,” and concluded “this is a huge undertaking.”

Michael T. Barrett, PhD, of TGen, pointed out that “each patient’s cancer could require it’s own specific therapy.” This was followed by Kurt Bachman of GlaxoSmithKline, who opined, “the challenge is to identify the tumor types most likely to respond, to find biomarkers that predict response, and to define the relationship of the predictors to biology of the inhibitors.”

What they were describing was precisely the work that clinical oncologists involved with cell culture assays have been doing for the past two decades. One of those clinicians, Dr. Robert Nagourney felt that there had been an epiphany.

The complexities and redundancies of human tumor biology had finally dawned on these investigators, who had previously clung unwaiveringly to their analyte-based molecular platforms.

The molecular biologists humbled by the manifest complexity of human tumor biology had finally recognized that they were outgunned and whole-cell experimental models had gained the hegemony they so rightly deserved.

Source: Dr. Robert A. Nagourney, medical director, Rational Therapeutics and instructor in Pharmacology at the University of California, Irvine School of Medicine. He posted about this on his blog.

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Although the theory behind targeted therapy is appealing, the reality is more complex. For example, cancer cells often have many mutations in many different pathways, so even if one route is shut down by a targeted treatment, the cancer cell may be able to use other routes.

In other words, cancer cells have 'backup systems' that allow them to survive. The result is that the drug does not shrink the tumor as expected. One approach to this problem is to functionally target multiple pathways in a cancer cell.

Another challenge is to identify which of the targeted treatments will be effective (enzyme inhibitors, proteasome inhibitors, angiogenesis inhibitors, and monoclonal antibodies).

Targeted therapy is still trial-and-error treatment.

The functional profiling platform can explore multiple signaling pathways from the same test. It doesn't have to test for each and every signaling pathways there are.

There are many pathways to altered cellular function. Testing for these pathways, those which identify DNA, or RNA sequences or expression of individual genes or proteins often examine only one component of a much larger, interactive process. In testing for all "known" mutations, if you miss just one, it may be the one that gets through.

And it's not just only targeted drugs that may be effective as first-line treatment on your individual cancer cells. Cancers share pathways across tumor types. There really is no lung cancer chemos, or breast cancer chemos, or ovarian cancer chemos.

There are chemos that are sensitive (effective) or there are chemos that are resistant (ineffective) to each and every "individual" cancer patient, not populations. There are chemos that share across tumor types.

The functional profiling platform has the unique capacity to identify all of the operative mechanisms of response and resistance by gauging the result of drug exposure at its most important level: cell death.

Finding what targeted therapies would work for what cancers is very difficult. A lot of trial-and-error goes along trying to find out. However, finding the right targeted therapies for the right "individual" cancer cells can be improved by cell-based assays, using functional profiling.

Identifying DNA expression of individual proteins (that measure of RNA content, like Her2, EGFR, KRAS or ALK) often examine only one component of a much larger, interactive process. Gene (molecular) profiling measures the expression only in the "resting" state, prior to drug exposure. There is no single gene whose expression accurately predicts clinical outcome. Efforts to administer targeted therapies in randomly selected patients often will result in low response rates at significant toxicity and cost.

Functional profiling measures proteins before and after drug exposure. It measures what happens at the end (the effects on the forest), rather than the status of the individual trees. Molecular profiling is far too limited in scope to encompass the vagaries and complexities of human cancer biology when it comes to drug selection. The endpoints of molecular profiling are gene expression. The endpoints of functional profiling are expression of cell death (both tumor cell death and tumor associated endothelial [capillary] cell death).

In testing for all "known" mutations, if you miss just one, it may be the one that gets through. And it's not just only targeted drugs that may be effective as first-line treatment on your "individual" cancer cells. Cancers share pathways across tumor types.

Targeted treatments take advantage of the biologic differences between cancer cells and healthy cells by "targeting" faulty genes or proteins that contribute to the growth and development of cancer. Many times these drugs are combined with chemotherapy, biologic therapy (immunotherapy), or other targeted treatments.

Clinicians have learned that the same enzymes and pathways are involved in many types of cancer. However, understanding targeted treatments begins with understanding the cancer "cell." In order for cells to grow, divide, or die, they send and receive chemical messages. These messages are transmitted along specific pathways that involve various genes and proteins in the cell.

Cancer cells often have many mutations in many different pathways, so even if one route is shut down by a targeted treatment, the cancer cell may be able to use other routes.

Targeted therapies are typically not very effective when used singularly or even in combination with conventional chemotherapies. The targets of many of these drugs are so narrow that cancer cells are likely to eventually find ways to bypass them.

Physicians may have to combine several targeted treatments to try an achieve cures or durable responses for more complicated tumors like those that occur in the breast, colon and lung.

These targeted therapies produce limited results because they can help a relatively small subgroup of cancer patients. But when they work, they produce very good responses. With targeted therapy, the trick is figuring out which patients will respond. Tests to pinpoint those patients cannot be accomplished with genetic testing.

All the gene amplification studies, via genetic testing, tell us is whether or not the cancer cells are potentially susceptible to a mechanism/pathway of attack. They don't tell you if one drug is better or worse than another drug which may target a certain mechanism/pathway. Cell-based functional analysis can accomplish this.

The cell is a system, an integrated, interacting network of genes, proteins and other cellular constituents that produce functions. You need to analyze the systems' response to drug treatments, not just one target or pathway, or even a few targets/pathways.

Literature Citation:

Functional profiling with cell culture-based assays for kinase and anti-angiogenic agents Eur J Clin Invest 37 (suppl. 1):60, 2007

Functional Profiling of Human Tumors in Primary Culture: A Platform for Drug Discovery and Therapy Selection (AACR: Apr 2008-AB-1546)

Chasing Gene Mutations http://cancerfocus.org/forum/showthread.php?t=3620

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Symposium on Circulating Tumor Cells and Chemosensitivity Testing

Santa Monica, December 7–9, 2011

Robert Nagourney, MD, founder of Rational Therapeutics, Inc., Long Beach, CA, was a featured speaker at The Symposium on Circulating Tumor Cells and Chemosensitivity Testing, December 7 – 9, at Loews Beach Hotel, Santa Monica, CA.

The academic conference was sponsored by the Angeles Clinic Foundation, as a result of a generous gift from the Farrah Fawcett Foundation. Fawcett died in 2009 at St. John’s Health Center after a lengthy battle against cancer, but was a believer in what is being called Personalized Cancer Cytometrics -- a decision by investigators in the field, who decided that they should actually come up with a name which everyone will agree to use.

This was the first symposium of it's kind to be offered in the world and the development of this type of technology was the hope and dream of Farah Fawcett whose foundation has supported the development of this symposium. Ms. Fawcett had chemotherapy through the John Wayne Cancer Institute of which The Angeles Clinic is affiliated.

The invitation only symposium brought together the world’s prominent researchers in this area in order to raise awareness and explore current methods of cancer treatment including assays. Although the symposium was a very closed affair, a formal "White Paper" is being produced and a there may be a formal peer-reviewed publication coming out of it.

Dr. Nagourney, a board certified oncologist and hematologist and noted expert on chemosensitivity testing for more than 20 years, will highlight the lack of progress made in this arena due in part to the politics and economics of cancer treatment. “Physicians tend to follow standardized guidelines or ‘off the shelf treatments’ that provide the same traditional chemotherapy agent to every cancer patient. The treatments work adequately well, the schedules are established, the toxicities are well known, and no one is cured.”

Dr. Nagourney, who recently addressed the situation at a TEDx symposium, sees an overwhelming need to spread the message this conference addressed – using cell-death cell culture assays, which provide a functional profile of how the cancer will respond to treatment.

Dr. Nagourney says, “Combining diagnostic skill with scientific insight, the physician becomes the captain of the ship.” He adds that assay-directed approaches can provide objective data that is then used to guide treatment selections. “Predicated upon an understanding of the patient’s tumor biology, cancer therapy becomes an intellectual exercise that draws upon literature and a knowledge of pharmacology and physiology,” he says.


As there had been a death in my family, my ability to attend the entire conference was limited and I could only particpate the afternoon session. The symposium included several areas of investigation, including circulating tumor cell analysis, molecular profiling and functional analytic platforms. I had the opportunity to sit in on several presentations including one by Dr. Weisenthal, who gave an overview of his seminal contributions to the field followed by his discussion of his work on VEGF inhibition and the crosstalk between other classes of tyrosine kinase inhibitors and endothelial (vascular) cell viability. Dr. Presant gave a presenation on their work with the MiCK assay, with a focus upon leukemia studies and their developing work on solid tumors. My impression is that we made a fundamental transition. In the past I was repeatedly confronted by oncologists who said: ”We could not do this.” Today the question appears to be more: “How best can we do this?" In that regard there has been progress. - Robert Nagourney

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Dr. Mario Lacouture from Memorial Sloan-Kettering Center Center in New York and his colleagues from the Northwestern University Feinberg School of Medicine in Chicago, have suggested in a new study that painful rashes and other skin-related side effects of newer targeted cancer drugs may jack up treatment costs.

The average cost of treating each cancer patient who came into a dermatology clinic with skin, hair and nail complaints was almost $2,000, the researchers reported. That included expenses related to doctors' appointments, dermatology medications and lab tests. And some patients with skin problems may have to delay or alter their treatment regimen if side effects are too severe.

According to Dr. Lacouture, dermatologic side effects including skin irritation and dry skin are the two topmost concerns that patients have that they did not expect during therapy. Patients are prepared to get hair loss, they are prepared to get some nausea and diarrhea, but they aren't expecting to get is all these skin issues.

Lacouture and his colleagues tracked costs related to skin reactions in 132 patients being treated with targeted cancer-fighting drugs at their dermatology clinic between 2005 and 2008. The majority of those patients had colon or lung cancer and the most common drug treatments included Erbitux (cetuximab) and Tarceva (erlotinib).

Patients came in with a range of dermatology-related complaints, including painful acne, lesions and blisters on the hands and feet and nail infections. Those conditions cost anywhere from $21 to almost $11,000 to treat, depending on the patient.

The average total cost of medications, clinic visits, treatment procedures and lab tests such as blood work and wound culturing for each patient was $1,920. Dermatology drugs accounted for the greatest chunk of that, costing an average of about $840 per patient, according to findings published in the Archives of Dermatology.

Lacouture said that more than half of patients may have skin, hair and nail reactions to newer drugs that treat some of the most fatal types of cancer. That's because along with their cancer-fighting action, the drugs also attack proteins on the skin.

If skin reactions are severe, especially with certain cancer drugs including Nexavar (sorafenib) for kidney cancer, doctors may have to adjust dosages or take patients off those drugs for a period of time. While most of the extra costs would be covered by patients' insurance, skin problems also mean more time and transportation for appointments and co-payments.

It adds to the out-of-pocket costs for the patient and to the already ballooning cost of cancer. Those costs should be taken into consideration when evaluating new cancer drugs. The most important thing for patients is to be aware of how common these problems are and know that the sooner they are diagnosed and treated for side effects, the less likely it will interfere with cancer treatment and the quality of life.

Source: Archives of Dermatology, December 19, 2011.

http://archderm.ama-assn.org/cgi/conten ... 47/12/1403

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