Chemosensitivity Testing – What It Is and What It Isn’t

Several weeks ago I was consulted by a young man regarding the management of his heavily pre-treated, widely metastatic rectal carcinoma. Upon review of his records, it was evident that under the care of both community and academic oncologists he had already received most of the active drugs for his diagnosis. Although his liver involvement could easily provide tissue for analysis, I discouraged his pursuit of an ex vivo analysis of programmed cell death (EVA-PCD) assay. Despite this, he and his wife continued to pursue the option.

As I sat across from the patient, with his complicated treatment history in hand, I was forced to admit that he looked the picture of health. Wearing a pork pie hat rakishly tilted over his forehead, I could see few outward signs of the disease that ravaged his body. After a lengthy give and take, I offered to submit his CT scans to our gastrointestinal surgeon for his opinion on the ease with which a biopsy could be obtained. I then dropped a note to the patient’s local oncologist, an accomplished physician who I respected and admired for his practicality and patient advocacy.

A week later, I received a call from the patient’s physician. Though cordial, he was puzzled by my willingness to pursue a biopsy on this heavily treated individual. I explained to him that I was actually not highly motivated to pursue this biopsy, but instead had responded to the patient’s urging me to consider the option of performing an EVA-PCD assay. I agreed with the physician that the conventional therapy options were limited but noted that several available drugs might yet have a role in his management including signal transduction inhibitors.

I further explained that some patients develop a process of collateral sensitivity, whereby resistance to one class of drugs (platins, for example) can enhance the efficacy of other class of drugs (such as, antimetabolite) Furthermore, patients may fail a drug, then be treated with several other classes of agents, only then a year of two later, manifest sensitivity to the original drug.

Blog artOur conversation then took a surprising turn. First, he told me of his attendance at a dinner meeting, some 25 years earlier, where Dan Von Hoff, MD, had described his experiences with the clonogenic assay. He went on to tell me how that technique had been proven unsuccessful finding a very limited role in the elimination of “inactive” drugs with no capacity to identify “active” drugs. He finished by explaining that these shortcomings were the reason why our studies would be unlikely to provide useful information.

I found myself grasping for a handle on the moment. Here was a colleague, and collaborator, who had heard me speak on the topic a dozen times. I had personally intervened and identified active treatments for several of his patients, treatments that he would have never considered without me. He had invited me to speak at his medical center and spoke glowingly of my skills. And yet, he had no real understanding of what I do. It made me pause and wonder whether the patients and physicians with whom I interact on a daily basis understand the principles of our work. For clarity, in particular for those who may be new to my work, I provide a brief overview.

1.    Cancer patients are highly individual in their response to chemotherapies. This is why each patient must be tested to select the most effective drug regimen.
2.    Today we realize that cancer doesn’t grow too much it dies too little. This is why older growth-based assays didn’t work and why cell-death-based assays do.
3.    Cancer must be tested in their native state with the stromal, vascular and inflammatory elements intact. This is why we use microspheroids isolated directly from patients and do not grow or subculture our specimens.
4.    Predictions of response are not based on arbitrary drug concentrations but instead reflect the careful calibration of in vitro findings against patient outcomes – the all-important clinical database.
5.    We do not conduct drug resistance assays. We conduct drug sensitivity assays. These drug sensitivity assays have been shown statistically significantly to correlate with response, time to progression and survival.
6.    We do not conduct genomic analyses for there are no genomic platforms available today that are capable of reproducing the complexity, cross-talk, redundancy or promiscuity of human tumor biology.
7.    Tumors manifest plasticity that requires iterative studies. Large biopsies and sometimes multiple biopsies must be done to construct effective treatment programs.
8.    With chemotherapy, very often more is not better.
9.    New drugs are not always better drugs.
10.  And finally, cancer drugs do not know what diseases they were invented for.

While we could continue to enumerate the principles that guide our practice, one of the more important principles is humility. Medicine is a humbling experience and cancer medicine even more so. Patients often know more than their doctors give them credit for. Failing to incorporate a patient’s input, experience and wishes into the treatment programs that we design, limits our capacity to provide them the best outcome.

With regard to my colleague who seemed so utterly unfamiliar with these concepts, indeed for a large swath of the oncologic community as a whole, I am reminded of the saying “There’s none so blind as those who will not see.”

Reposted from March 23, 2012

What is Personalized Cancer Therapy?

Personalized therapy is the right treatment, at the right dose for the right patient. Like the weather, however, it seems that everyone’s talking about it, but no one is doing anything about it.

In its simplest form personalized care is treatment that is designed to meet an individual’s unique biological features. Like a key in a lock, the right drug or combination opens the door to a good outcome.

Lock & Keys 1When over the years I lectured on the development of the cisplatin/gemcitabine doublet, my two boys were quite young. I would show a slide depicting a doorknob with a key in the keyhole. I likened our lab’s capacity to identify sensitivity to the cisplatin/gemcitabine combination as “unlocking” an individual’s response.

At the time my wife and I would leave the key in the inside of the front door enabling us to unlock it when going out. We reasoned at the time that our 2-year-old would not be strong enough, nor tall enough to turn the key and let himself outside. We reasoned wrong, for one day our son Alex reached up, turned the key and opened the door right in front of us. Lesson learned: Given the right key, anyone can open a door.

I continued my analogy by saying that even Arnold Schwarzenegger would be unable to open a door given the wrong key, but might, if he continued trying, snap it off in the lock.

The right key is the right treatment, effortlessly unlocking a good response, while the wrong key is the wrong treatment more often than not too much, too late, akin to a solid tumor bone marrow transplant.

In recent years, personalized care has come to be considered synonymous with genomic profiling. While we applaud breakthroughs in human genomics today, there is no molecular platform that can match patients to treatments. The objective response rate of just 10 percent, almost all in breast and ovarian cancer patients in one study (Von Hoff J Clin Oncol 2010 Nov 20:28(33): 4877-83), suggests that cancer biology is demonstrably more complex than an enumeration of its constituent DNA base pairs. The unilateral focus on this area of investigation over others might be described as “the triumph of hope over experience” (James Boswell, Life of Samuel Johnson, 1791).

But hope springs eternal and with it the very real possibility of improving our patients outcomes. By accepting, even embracing, the complexity of human tumor biology we are at the crossroads of a new future in cancer medicine.

William Withering (1741-1799) the English physician and botanist credited with discovering digitalis as the therapy for dropsy, e.g. congestive heart failure (An Account of the Foxglove and some of its Medical Uses, Withering W. 1785), had absolutely no idea what a membrane ATPase was, when he made his remarkable discovery. It didn’t matter. Cardiac glycosides provided lifesaving relief to those who suffered from this malady for fully two centuries before Danish scientist, Jens Christian Skou, identified these membrane bound enzymes, for which he was awarded a Nobel Prize in 1997.

Similarly, penicillin, aspirin, and morphine were in all use for decades, centuries, even millenia before their actual modes of action were unraveled. Medical doctors must use any and all resources at their disposal to meet the needs of their patients. They do not need to know “how” something works so much as they (and their patients) need to know “that” it works.

The guiding principle of personalized medicine is to match patients to therapies. Nowhere in this directive is there a prescription of the specific platform to be used. Where genomic signatures provide useful insights for drug selection, as they do in APL (ATRA, Arsenic trioxide); NSCLC (EGFr, ROS1, ALK); CML (Imatinib, Dasatanib) then they should be used.

However, in those disease where we haven’t the luxury of known targets or established pathways, i.e. most human malignancies, then more global assessments of human tumor biology should, indeed must, be used if we are to meet the needs of our patients. Primary culture analyses like the EVA-PCD® provide a window onto human tumor biology. They are vehicles for therapy improvement and conduits for drug discovery. Scientists and clinicians alike need to apply any and all available methodologies to advance their art. The dawn of personalized medicine will indeed be bright if we use all the arrows in our quiver to advance clinical therapeutics and basic research.

Reposted from May 2012

What Can You Do to Improve Your Odds Against Cancer?

I sometimes joke with my patients that a new diagnosis of cancer rarely provides them enough time to get an MD or PhD. Yet it is that level of preparation that may be required to answer the myriad questions that lie ahead.

Although it’s a joke, it is only partly in jest. Unlike buying a house or a car for which one’s life experiences can prepare you, medicine is opaque, complicated and ever changing. At the bleeding edge of medical complexity sits medical oncology and its dizzying array of genomics, transcriptomics, proteomics, epigenomics and metabolomics. Not only is it difficult for patients to keep up with all the changes, it is increasingly beyond the ken of their doctors who have spent entire careers training in the specialty, many of whom may have an MD and a PhD.

So how can patients improve their odds when the obstacles seem so daunting?

notebook-clipart-red-spiral-notebookMy first recommendation is that you develop a personal diary or record book of the procedures, staging studies, pathologic diagnosis, tumor markers, and physician recommendations. This can be accomplished by requesting that your doctors provide either electronic or physical copies of CT scans, pathology reports, blood tests and other clinically relevant information. While there has been some controversy surrounding their overuse, I am a believer in the simple blood tests used as barometers of your cancer with names like CEA, CA19.9, CA125, CA27.29, and CA 15.3. Although they are not perfect, they are easy to obtain, relatively inexpensive and can be repeated regularly to assess progress with therapy.

The second thing that I recommend is that you gain a working knowledge of your diagnosis. While there are no lung cancer search resultsperfect sources of information, the internet can provide useful basic information as a starting point. Begin by obtaining from your doctor the most accurate definition of the cancer. If it is breast cancer, is it infiltrating ductal or lobular? Are you ER positive? Is your tumor HER-2 positive? If it is stomach cancer, is it intestinal type or diffuse, etc? This will facilitate your searches, as well as your future conversations with consultants.

Once you know what you’ve got, the next thing you will need to know is where it is. That is what is known as your stage. The older classification used Roman Numerals I-IV with local disease (early) as stage I and metastatic (disseminated) as stage IV. The more modern system is known as TNM, where T stands for tumor size (1-4), N stands for lymph involvement(1-3), and M stands for metastatic involvement (0 or 1). Most contemporary pathology reports include TNM staging. With the diagnosis and stage established, you now know what you have and where it is.

This is where it gets interesting. Now, what do you do about it?

It is at this point that therapeutic choices must be made. Most physicians will rely upon standard established guidelines. Among the most widely used guidelines are those published by the National Comprehensive Cancer Network known as NCCN. While these guidelines can be useful, they can also be stultifying, limiting patients to what might be considered the lowest common denominator of care. While they may be better than haphazard treatment selection, they may very much miss the mark for your unique needs.

Here the process degenerates into a plethora of confusing choices.

Should you have genomic profiling? If so, should it be based on a tissue biopsy, circulating cell free tumor analysis, or even the newer urine tests that measure the presence or absence of abnormal genes? All of these technologies have merit and over the coming years the best ones will shake out. Despite these tests being widely touted (and profitable for the purveyors), none of these test have been put to formal trials that establish their capacity to influence survival. This is interesting because many of these tests have obtained insurance and Medicare coverage without even remotely rising to this standard. Nonetheless, these tests can be used for specific diseases like lung and leukemia where actionable targets are known to exist. Beyond that, caveat emptor (buyer beware).

One of the problems with genomic profiles is that they do very good job of telling you what the problem may be, but a very bad job at telling you the solution. It is a rare genomic mutation that comes with a drug to treat it. Most of the findings wind up asking more questions rather than providing more answers.

With the diagnosis established, the stage known and in certain circumstances molecular profiles complete, it is time for you to choose treatments and the centers that will provide them. Many seek the care of academic centers. These centers may offer clinical trials as a first line therapy for those who meet criteria.

NCI Clinical TrialsIt should be remembered that clinical trials are conducted in three principal formats. Phase I trials examine brand new drugs. These trials determine the safety of the drugs at different dose schedules. Phase II trials take the established safe doses and develop experience in each type of disease, e.g. lung versus colon versus breast. Phase III trials then compare the new drugs with existing treatments to see if there is any real improvement.

It is critical to recognize the functions of these different types of trials. Phase I studies classically have no therapeutic intent (your benefit is secondary to their measurement of your ability to tolerate the drug).

Phase II trials seek evidence of clinical activity by disease, but your specific disease may not be right for that drug.

Finally, Phase III allows a comparison of standard treatment to the new one. Many of these drugs do not make the grade and fall off the development wagon. In addition, you must be willing to be randomly assigned.

It is here that my approach diverges from those outlined. I have long maintained that each patient is unique and that their cancers must be treated individually. Recognizing that no genomic, proteomic or transcriptomic platform can answer the very complex questions of therapeutic response, we at Rational Therapeutics have developed functional analyses through the use of the EVA-PCA assay, which studies each patient’s tumor by exposing it to the drugs of interest. The most active, least toxic combinations are then recommended. In a report at the American Society of Clinical Oncology meeting of 2013, we showed a 2.02 higher response rate (P < 0.001) and a 1.44 improvement in one year survival (P < 0.02) for patients who received assay-guided therapy. This established the predicative validity of the functional approach.

It is important for patients to realize that cancer is an unbalanced system, not just an abnormal cell. Cancer as a disease goes beyond the cell or even the tumor to affect the body itself. Alterations in immunity, metabolism and physiology contribute to the good or bad outcomes of every patient. Patients should seek to normalize their lifestyle, improve their diets, maintain an active exercise program, reduce their weight to lean body weight, and may in some circumstances consider nutritional supplements and/or appropriately selected natural products that may augment their wellbeing.

The human body is a complicated machine and each part resonates with every other part. A good diet, a good night’s sleep and avoidance of an unhealthy lifestyle, as much as they may sound like your mother’s advice, is indeed very good advice.

Every cancer patient has the right to get better. As a patient, you should take charge of your cancer and make smart decisions. Afterall, no one is more interested in saving your life than you.

Practicing Clinical Oncologists to the Rescue

Cancer patients and their physicians can find themselves at the wrong end of many scientific discoveries. For example, the drug capecitabine, sold commercially as Xeloda, was originally marketed at a daily dose of 2500 mg/m2 given for two weeks.

This schedule developed by the pharmaceutical investigators, is known as the maximum tolerated dose (MTD) and it performed well against other regimens for breast and colon cancer. With an FDA approval in hand, oncologists began administering the drug on the recommended schedule.

MTD2It did not take long before physicians and their patients realized that 2500 mg/m2/day was more than many patients could tolerate. Hand-foot Syndrome (an inflammation of the skin of palms and soles), mucositis (oral ulcers) myelosuppression (lowered blood counts) and diarrhea were all observed. Immediately clinical physicians began to dose de-escalate. Soon these astute practitioners established more appropriate dose schedules and the drug found its rightful place as a useful therapeutic in many diseases.

What was interesting was that activity continued to be observed. It appeared that the high dose schedule was simply toxic and that lower doses worked fine, with fewer side effects.

Modern targeted agents have been introduced over recent years with dose schedules reminiscent of capecitabine. The drug sunitinib, approved for the treatment of renal cell carcinoma, is given at 50 mg daily for four weeks in a row, followed by a two week rest. Despite good activity, toxicities like mucositis and skin rash often set in by the third week. What remained unclear was whether these schedules were warranted. A recent report in the Annals of Oncology examined this very question. In a retrospective analysis of patients with kidney cancer the physicians found that lowering the dose of sunitinib preserved activity but reduced toxicity.

As a practitioner, I have long reduced my patient’s schedule of sunitinib to two weeks on, one week off or even 11 days on, 10 days off. In one patient that I treated for a gastrointestinal stromal tumor (GIST), I achieved a durable complete remission with just 25 mg/day, given seven days each month, a remission that persists to this day, seven years on.

We are in a new world of targeted therapy, one in which very few people understand the kinetics, pharmacodynamics and response profiles of patients for novel drugs. In our laboratory, favorable dose response curves often suggest that many agents could be administered at lower doses. More interestingly, some patients who do not carry the “targets” for these drugs nonetheless respond. This has broad implications for multi-targeted inhibitors like sunitinib that can influence multiple targets simultaneously.

As so often happens, it is the nimble clinical physicians with their feet on the ground, confronting the very real needs of their patients who can outmaneuver and outthink their academic colleagues. The trend toward consolidation in medicine and the absorption of clinical practices into hospital groups all using standardized algorithms has the risk of stifling the very independence and creativity of practicing oncologists that has proven both effective and cost-effective for our patients and our medical system at large.

Of Cells, Proteins and Cancer Drug Development

Our recent presentation at the American Association for Cancer Research meeting reported our work with a novel class of compounds known as the HSP90 inhibitors. AACR 2015-HSP90 Abstract

The field began decades earlier when it was found that certain proteins in cells were required to protect the function of other newly formed proteins hormone receptors and signaling molecules. Estrogen and androgen receptors, among others, require careful attention following their manufacture or they will find themselves in the cellular waste bin.

230px-Geldanamycin.svgAs each new protein is formed it risks digestion at the hands of a garbage disposal-like device known as a proteasome (named for its protein digesting capabilities). To the rescue comes HSP90 that chaperones these newly created proteins through the cell and protects them until they can assume their important roles in cell function and survival.

Recognizing that these proteins were critical for cell viability, investigators at Sloan-Kettering and others developed a number of molecules to block HSP90. The original compounds known as ansamycins underwent clinical trials with evidence of activity in some breast cancers. The next generation of compounds was tested in other diseases. Though the clinical results have been mixed, the concept remains attractive.

We compared two drugs of this type and showed that they shared similar function but had different chemical properties and that the concentrations required to kill cells differed. What is interesting is the activity of these drugs seems to be patient-specific. That is, each patient, whether they had breast or lung cancer, showed a unique profile that was not directly connected to the type of cancer they had. This has important implications.

Today, pharmaceutical companies develop drugs by disease type. Compounds enter Phase II trials with 30 to 50 lung cancer patients treated, then 30 to 50 breast cancer patients treated and so on. This continues until (it is hoped) one of the diseases provides a favorable profile and the data is submitted to the FDA for a disease-specific approval. As home runs are rare, most drugs never see the light of day failing to provide sufficient response in any disease to warrant the enormous expense of bringing them to market.

What we found with the HSP90 inhibitors is that some breast cancers are extremely sensitive while others are not. Similarly some lung cancers are extremely sensitive while others are resistant. This forces us once again to confront the fact that cancer patients are unique.

Pharmaceutical companies exploring the role of targeted agents like the HSP90 inhibitors must learn to incorporate patient individuality into the drug development process. Failing to do so not only risks the loss of billions of dollars but more importantly denies patients access to active novel agents.

The future of drug development can be bright if the pharmaceutical industry embraces the concept that each patient’s profile of response is unique and that these responses reflect patient-specific, not diagnosis-based drivers. Clinical trials must incorporate individual patient profiles. Drugs could be made more available once Phase I studies were complete by using biomarkers for response, such as the EVA-PCD assay, which has the capacity to enhance access and streamline drug development.

Cancer Research Moves Forward by Fits and Starts

AACR logoI recently returned from the American Association for Cancer Research (AACR) meeting held in Philadelphia. AACR is attended by basic researchers focused on the molecular basis of oncology. Many of the concepts reported will percolate to the clinical literature over the coming years.

There were many themes including the revolution in immunologic therapy that took center stage, as James Allison, PhD, received the Pezcoller Prize for his groundbreaking work in targeting immune checkpoints. The Princess Takamatsu Award given to Dr. Lewis Cantley, recognized his seminal contribution to our understanding of signal transduction at the level of PI3K. A series of very informative lectures were provided on “liquid biopsies” that examine blood, serum and other bodily fluids to characterize the process of carcinogenesis. These technologies have the potential to revolutionize the diagnosis and monitoring of cancers.

The first symposium I attended described the phenomenon of chromothripsis. This represents a catastrophic cellular trauma that results in the simultaneous fragmentation of chromosomal regions, allowing for rejoining of disparate chromosome components, often leading to malignancy and other diseases. I find the concept intriguing, as it reflects the intersection of oncology with evolutionary developmental biology, reminiscent of the outstanding work of Stephen Jay Gould. His theory of punctuated equilibrium, from 1972, challenged many long held beliefs in the study of evolution.

Since the time of Charles Darwin, we believed that evolution was slow and continual.  New attributes were selected under environmental pressure and the population carried those characteristics forward toward higher complexity. Gould and his associate, Niles Eldredge, stated that evolution was anything but gradual. Indeed, according to their hypothesis, evolution occurred as a state of relative stability, followed by brief episodes of disruption. This came to mind as I contemplated the implications of chromothripsis.

Licensed under CC BY-SA 3.0 via Wikimedia Commons

Licensed under CC BY-SA 3.0 via Wikimedia Commons

According to the new thinking (chromothripsis and its related fields), cancer may arise as a single cell forced to recover from what would otherwise be catastrophic injury. The reconfiguring of genetic elements scrambled together to avoid apoptosis (programmed cell death) provides an entirely new biology that can progress to full-blown malignancy.

By this reasoning, each patient’s cancer is unique. The results of damage control whereby chromosomal material is rejoined haphazardly would be largely unpredictable. These cancers would have a fingerprint all their own, depending on which chromosome was disrupted.

As high throughput technologies and next generation sequences continue to unravel the complexity of human cancer, we seem to be more and more like those who practice stone rubbing to create facsimiles of reality from the “surface” of our genetic information. Like stone rubbing, practitioners do not create the images, but simply borrow from them.

With each symposium, we learn that cancer biology does not come to be, but is. Grasping the complexity of cancer requires the next level of depth. That level of depth is slowly being recognized by investigators from Harvard University to Vanderbilt as the measurement of humor tumor phenotypes.

Cancer is phenotypic and human biology is phenotypic. Laboratory analyses that allow us to measure, grasp, and manipulate phenotypes are those that will provide the best outcomes for patients. Laboratory analyses like the EVA-PCD.

Is Cancer a Genetic Disease?

I recently had the opportunity to meet two charming young patients: One, a 32-year-old female with an extremely rare malignancy that arose in her kidney and the other a 33-year-old gentleman with widely metastatic sarcoma.

Both patients had obtained expert opinions from renowned cancer specialists and both had undergone aggressive multi-modality therapies including chemotherapy, radiation and surgery. Although they suffered significant toxicities, both of their diseases had progressed unabated. Each arrived at my laboratory seeking assistance for the selection of effective treatment.

Sarcoma 130412.01With the profusion of genomic analyses available today at virtually every medical center, it came as no surprise that both patients had undergone genetic profiling. What struck me were the results. The young woman had “no measurable genetic aberrancies” from a panoply of 370 cancer-causing exomes, while the young man’s tumor revealed no somatic mutations and only two germ-line SNV’s (single nucleotide variants) from a 50 gene NextGen sequence, neither of which had any clinical or therapeutic significance.

What are we to make of these findings? By conventional wisdom, cancer is a genetic disease. Yet, neither of these patients carried detectable “driver” mutations. Are we to conclude that the tumors that invaded the cervical vertebra of the young woman, requiring an emergency spinal fusion, or the large mass in the lung of the young man are not “cancers”? It would seem that if we apply contemporary dogma, these patients do not have a cancer at all. But nothing could be further from the truth.

Cancer as a disease is not a genomic phenomenon. It is a phenotypic one. As such, it is extremely likely that these patients’ tumors are successfully exploiting normal genes in abnormal ways. The small interfering RNAs or methylations or acetylation or non-coding DNA’s that conspired to create these monstrous problems are too deeply encrypted to be easily deciphered by our DNA methodologies. These changes are effectively gumming up the works of the cancer cell’s biology without leaving a fingerprint.  Slide Detail-small

I have long recognized that cellular studies like the EVA-PCD platform provide the answers, through functional profiling, that genetic analyses can only hope to detect. The assay did identify drugs active in these patients’ tumor, which will offer meaningful benefit, despite the utter lack of genetic targets. Once again, we are educated by cellular biology in the absence of genomic insights. This leaves us with a question however – is cancer a genetic disease?

The Emperor of All Maladies’ New Clothes

Ken Burn’s series “The Emperor of All Maladies” from Siddhartha Mukherjee’s book of the same title ppbs logorovides an interesting and informative historical perspective on mankind’s efforts to confront cancer as a disease.

Beginning with ancient references to human malignancy, the series goes on to explore radical surgery and the earliest use of radiation but really gains traction in the mid-20th century with the discovery of the first chemotherapy drugs. While the nitrogen mustard derivatives were being studied under a veil of military secrecy, Dr. Sidney Farber in Boston explored the B-vitamin analogue, aminopterin, for the treatment of childhood leukemia. (You can read more about this in my book Outliving Cancer.)

Through the ensuing decades, seemingly stunning victories ultimately fell in crushing defeats, while the promise of single agents, then multi-drug combinations, followed by dose-intensive therapies, and finally bone marrow transplantation yielded few cures but delivered ever increasing toxicities. Clifton Leaf, a cancer survivor himself who created a stir with his controversial 2003 Fortune Magazine article entitled “Why We Are Losing the War on Cancer and How to Win It” described his own disappointment with the slow pace of progress.

Screen shot Emperor of All MaladiesThe last episode examined our growing understanding of human genomics and segued by interviews with Richard Klausner, former director of the National Cancer Institute; and Harold Varmus, the current NCI director; to Michael Bishop, Eric Lander and Francis Collins who luxuriated in the clinical potential of human genomics and the coming era of big science.

The final part was an interview with Steven Rosenberg, one of the earliest pioneers in immunotherapy and Carl June whose groundbreaking work with chimeric antigen receptor T-cells is among the most recent applications of this important field.

The take-home message would seem to be that despite the fits and starts we are now at the dawn of a new age of big science, big data and genomic breakthroughs. What was missing however was an examination of where we had gone wrong. It would seem that the third rail for this community is an honest assessment of how a small coterie of investigators who championed only certain ways of thinking over all others commandeered all the money, grants, publications, chairmanships and public attention, while patients were left to confront a disease from which survival has changed very little, at ever increasing costs and toxicities.

Another thing that came through was the very human side of cancer as a disease and the kindness and emotional support that family members and parents provided to those afflicted. I couldn’t help but feel that these individuals had been cheated: cheated of the lives of their family members, cheated of the resources that could have pursued other options and cheated of the well-being that these poisonous and dose-intensive regimens rained upon them in their last days.

As science has become the new religion and scientists the new gurus, one message that resonated was that many of these gurus were false prophets. They are too self-absorbed to question their own dogmatic belief systems in dose-intensity or multi-agent combinations, all of which fell painfully by the way side as the next therapeutic fad emerged. Will our current love affair with the gene prove to be little more than the most current example of self-congratulatory science conducted in the echo chamber of modern academia?

Victories against cancer will be won incrementally. Each patient must be addressed as an individual, unique in their biology and unique in their response probability. No gene profile, heat map, DNA sequence or transcriptomic profile has answered the questions that every patient asks; “What treatment is best for me?” Dr. Mukherjee himself used the analogy of the blind men and the elephant. Unfortunately, there was little discussion of how much that parable may apply to our current scientific paradigms.

It is time for patients to demand better and refuse to participate in cookie-cutter protocols.
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Physicians should become more familiar with the fundamentals of physiology and biochemistry to better understand the principles of cancer prevention at the level of diet and lifestyle.

Finally, while we wait with bated breath, for the arrival of glorious gene profiles widely touted as the future answer to all of cancer’s most vexing questions, patients should throw off the yoke of one-size-fits-all approaches and demand laboratory platforms, such as the EVA-PCD assay, that are available today to make better use of existing treatments.

Interview with CCTV Now Available

nagourney3This Saturday, April 4, my interview on CCTV’s program FULL FRAME will be aired.
The Mike Walters interview focuses on my study of human cancer using the 3-D microspheroid EVA-PCD platform. We review the excellent patient outcomes associated with the use of this technology to select chemotherapy drugs and targeted agents.

The program streams live online Sat. at 4 p.m.  http://www.cctv-america.com/livenews

The program is already available on the CCTV menu of videos at: http://www.cctv-america.com/videos   Scroll down the list of available programming until you see Cancer Treatments: One size does not fit all.

CCTV is an international network with millions of viewers. The program, Full Frame, is a news magazine format that conducts in-depth interviews involving current topics of interest.

Is There a Role for PI3k Inhibitors in Breast Cancer? Maybe.

Over the past decades oncologists have learned that cancer is driven by circuits known as signal transduction pathways. Signal_transduction_pathways.svgThe first breakthroughs were in chronic myelogenous leukemia (CML) where a short circuit in the gene as c-Abl caused the overgrowth of malignant blasts. The development of Imatinib (Gleevec) a c-Abl inhibitor yielded brilliant responses and durable remissions with a pill a day.

The next breakthrough came with the epidermal growth factor pathway and the development of Gefitinib (Iressa) and shortly thereafter Erlotinib (Tarceva). Good responses in lung cancers, many durable were observed and the field of targeted therapy seemed to be upon us.

220px-PI3kinaseAmong the other signal pathways that captured the imagination of the pharmaceutical industry as a potential target was phospho-inositol-kinase (PI3K). Following experimental work by Lew Cantley, PhD, who first described this pathway in 1992, more than a dozen small molecules were developed to inhibit this cell signal system.

The PI3K pathway is important for cell survival and regulates metabolic activities like glucose uptake and protein synthesis. It is associated with insulin signaling and many bio-energetic phenomena. The earliest inhibitors functioned downstream at a protein known as mTOR, and two have been approved for breast, neuroendocrine and kidney cancers. Based on these early successes, PI3K, which functions upstream and seemed to have much broader appeal, became a favored target for developmental clinical trials.

The San Antonio Breast Cancer Symposium is one of the most important forums for breast cancer research. The December 2014 meeting featured a study that combined one of the most potent PI3K inhibitors, known as Pictilisib, with a standard anti-estrogen drug, Fulvestrant, in women with recurrent breast cancer. The FERGI Trial only included ER positive patients who had failed prior treatment with an aromatase inhibitor (Aromasin, Arimidex or Femara). The patients were randomized to receive the ER blocker Fulvestrant with or without Pictilisib.

With seventeen months of follow-up there was some improvement in time to progressive disease, but this was not large enough to achieve significance and the benefit remains unproven. A subset analysis did find that for patients who were both ER (+) and PR (+) a significant improvement did occur. The ER & PR (+) patients benefitted for 7.4 months on the combination while those on single agent Fulvestrant for only for 3.7 months.

The FERGI trial is more interesting for what it did not show. And that is that patients who carried the PI3K mutation, the target of Pictilisib, did not do better than those without mutation (known as wild type). To the dismay of those who tout the use of genomic biomarkers like PI3K mutation for patient drug selection, the stunning failure to identify responders at a genetic level should send a chill down the spine of every investor who has lavished money upon the current generation of genetic testing companies.

It should also raise concerns for the new federal programs that have designated hundreds of millions of dollars on the new “Personalized Cancer Therapy Initiatives” based entirely on genomic analyses. The contemporary concept of personalized cancer care is explicitly predicated upon the belief that genomic patient selection will improve response rates, reduce costs and limit exposure to toxic drugs in patients unlikely to respond.

This unanticipated failure is only the most recent reminder that genomic analyses can only suggest the likelihood of response and are not determinants of clinical outcome even in the most enriched and carefully selected individuals. It is evident from these findings that PI3K mutation alone doesn’t define the many bioenergetic pathways associated with the phenotype. This strongly supports phenotypic analyses like EVA-PCD as better predictors of response to agents of this type, as we have shown in preclinical and clinical analyses.

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