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.

As 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

I 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

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 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. The 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.

Among 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.

Cancer Patients Need Answers Now!

I read a sad editorial in the Los Angeles Times written by Laurie Becklund, former LA Times journalist. It is, in essence, a self-written obituary as the patient describes her saga beginning almost 19 years earlier, when she detected a lump in her breast. With stage I breast cancer she underwent standard therapy and remained well for 13 years until recurrence was heralded by disease in bone, liver, lung and brain. Given a dire prognosis she became a self-made expert, conducting research, attending conferences, and joining on-line forums under the name “Won’t Die of Ignorance.” Despite her heroic effort Ms. Becklund succumbed to her illness on February 8. She was 66.

Ms. Becklund experienced the anguish that every patient feels when his or her own individual and highly personal needs simply aren’t being addressed. She opines that entities like the Susan G. Komen Fund, which has raised over $2.5 billion in the last 20 years, “channels only a fraction of those funds into research or assistance to help those who are already seriously sick.” She continues, “We need people, patients, doctors, scientists, politicians, industry and families to make a fresh start.” Her frustration is palpable as she states her outcome seemed to be based on the roll of the dice, like playing “Chutes and Ladders.”

The author’s plight is shared by the millions of patients who are confronting advanced cancers. They are not interested in “why” or “how” their cancers came to be. They can no longer benefit from early detection or cancer awareness campaigns. They need practical, actionable, clinical answers today.

Ms. Becklund’s commentary resonates with me and with everyone who has cancer or knows someone who does. As an oncology fellow at Georgetown, I found myself losing patient after patient to toxic and largely ineffective treatments, all despite my best efforts. I described this in my book “Outliving Cancer.” It was then that I decided that I would dedicate myself to meeting the individual needs of each of my patients and I have used a laboratory platform (EVA-PCD) to do so. I have encountered surprising resistance from clinicians and researchers who seem to prefer the glacial pace of incremental advancement found in population studies over individual solutions found in the study of each patient’s unique biology. Ms. Becklund correctly points out that every treatment must meet each individual’s need.

The role of the scientist is to answer a question (treatment A vs. treatment B) while that of the clinical physician must be to save a life. Every patient is an experiment in real time. It may well be that no two cancer patients are the same. Indeed, the complexity of carcinogenesis makes it very possible that every patient’s cancer is an entirely new disease, never before encountered. Although cancers may look alike, they may be biologically quite distinct. Meaningful advances in cancer will only occur when we learn to apply all available technologies to treat patients as the individuals that they are. Let us hope that Ms. Becklund’ s final essay does not fall upon deaf ears.

A New Use for One of the Oldest “New” Drugs

With the profusion of new targeted agents entering the clinical arena, a report from the American Society of Hematology bears consideration.

The trial known as the SORAML trial enrolled 276 patients with newly diagnosed acute myelogenous leukemia. The patients were between the ages of 18 and 60. All patients received a standard chemotherapy regimen. The patients were then randomized to receive Sorafenib or placebo. Patients on the Sorafenib arm then remained on a maintenance therapy for twelve months.

While the achievement of complete remission was almost identical between the two arms at 59% and 60%, the event free survival demonstrably favored the Sorafenib group at 20.5 months versus 9.2 months. At three years of follow-up 40% of the Sorafenib group were well with only 22% of the placebo group still in remission. This corresponds to a three-year relapse free survival of 38% for placebo and 56% for Sorafenib (P=0.017).

The results are of interest on several levels.
1.    Sorafenib a multitargeted tyrosine kinase inhibitor was approved in December 2005 for the treatment of renal cell carcinoma. This makes Sorafenib one of the first targeted agents to achieve FDA approval.

2.     Sorafenib has many modes of action and it is not entirely clear which of its functions were responsible for the superior survival in this AML study.

3.    Sorafenib’s approval reflects a rather convoluted and interesting history. When first developed the drug was designed to target the oncogene B-Raf. As a result the drug was introduced into early clinical trials for the treatment of advanced melanoma, a disease known to be associated with B-Raf mutation. As the drug proved ineffective, it appeared unlikely to gain FDA approval. That is, until it showed cross reactivity with VEGF pathway associated with tumor cell vascularity. A successful trial published in the New England Journal of Medicine then led to the approval.

Now, nine years later this old new drug has gained new life. This time in acute myelogenous leukemia.

The term “dirty drug” refers to agents that target many kinases at the same time. Sorafenib is an example of a “dirty drug.” However it is Sorafenib’s “dirty drug” quality that led first to its approval and most likely now leads to its application in AML. This reflects the fact that Sorafenib may be inhibiting B-Raf signaling associated with the common mutation in Ras upstream of B-Raf or it may reflect Flt3 a secondary activity associated with Sorafenib.

Indeed B-Raf and Flt3 may not be upregulated in every patient, but could serve a function of permissive activity granting an additional survival signal to the AML cells as they go through induction therapy. These subtleties of drug effect may escape genomic analysis as the true “target” may not be mutated, upregulated or amplified. No doubt the investigators in this study will conduct gene sequencing to determine whether there is a driver mutation associated with the advantage reported in this clinical study. What will be intriguing is to determine whether that advantage is an abnormal gene functioning within these cancerous cells or possibly a normal gene functioning abnormally in these cancer cells. More to come.

The Case for the Metabolic Basis of Cancer Gains Traction

Researchers from the Huntsman Cancer Institute at the University of Utah reported an interesting finding with far-reaching implications.

In their study of the rare tumor known as alveolar soft part sarcoma (ASPS), they examined the well-established chromosomal translocation that occurs between chromosomes 17 and X. This results in the production of a fusion protein dubbed ASPSCR1-TFE3. Like other fusion proteins described in malignancies such as lymphoma, acute pro-myelocytic leukemia and chronic myelogenous leukemia, a novel function occurs when two disparate genomic elements are spliced together.

In this instance, the ASPSCR1-TFE3 gene product functions as a lactate transporter. Strikingly, every mouse in which the gene was up regulated developed a tumor. The locations of tumor, in the skull and near the eye, both represented areas of high lactate concentration. In humans, this tumor occurs in skeletal muscle, also associated with high lactate production.

Since 1930, when Otto Warburg first described increased glycolysis (preferential use of sugars) in tumor cells, investigators have pondered the implication of inefficient glucose metabolism in the face of adequate oxygenation.

Human metabolism relies upon mitochondrial function to efficiently liberate the maximum amount of energy in the form of ATP from each glucose molecule. Glycolysis occurring in the cell cytoplasm is highly inefficient and produces only 1/18 of the amount of ATP that a full molecule of glucose can produce through mitochondrial oxidative phosphorylation. Recent molecular biological studies have established that the preferential use of glycolysis may represent the cells need to direct glucose away from energy production and toward the creation of essential structures like amino acids, lipids, and nucleic acids. With the rapid turnover of glucose, cells produce an overwhelming amount of lactate, which is then transported out of the cell. At least this has been the working hypothesis over many years.

More recently, investigators have begun to examine how lactate metabolism may represent the interplay between stromal fibroblast cells and tumor cells. Indeed, many tumor cells are now known to increase lactate uptake reflecting increased lactate production by fibroblasts that have been commandeered in the tumor microenvironment.

Lactate uptake is under the control of a family of transporters known as monocarboxylate transporters, of which nine have been described. These are expressed differently in various tissues, have different affinities for lactate and transport in one direction or another. These processes appear to be under the control of the major regulator of oxygen metabolism known as HIF-1 alpha. As cancer cells adapt to a high lactate environment, they can survive in low oxygen tension.

The preferential use of lactate as a source of energy is contrary to many dictates of current metabolic research that suggest that tumor cells preferentially use glucose and have limited capacity to utilize non-glucose energy sources like the ketone bodies acetoacetate and beta-hydroxybutyrate. Substantial literature on ketogenic diets suggests that these ketone bodies deprive cancer cells of needed nutrition and energy. The current discovery by the Utah investigators, as well as interesting work conducted by researchers in Italy on the prostate cancer, provide a new angle on some of these principles of cancer metabolism.

As the investigators from Utah note, the alveolar soft part sarcoma is a rare tumor, but the implications of these findings could be profound, as they force us to re-think tumorigenesis and the metabolic basis of cancer.

Future (Cancer) Shock

Two related clinical trials were reported in the last several months describing the use of heat shock protein 90 (HSP90) inhibitors in lung cancer. Both trials fell short of their pre-specified endpoints casting a pall upon these drugs. However, the study of HSP90 inhibitors should not be abandoned based on these finding, as this is a fertile area of investigation and offers opportunities for the future.

Human cells marshal many defenses against stress. Thermal injury can damage basic cellular functions by denaturing (inactivating) proteins. The machinery of cells is largely comprised of protein enzymes. Excessive heat coagulates proteins much the way the albumin of an egg turns white during cooking. The loss of fluidity and function ultimately results in cell death. The heat shock proteins come to the rescue by shepherding these proteins away from injury and protecting them from denaturation.

There are many different heat shock proteins found in human cells, but one of the most abundant and active in cancer cells is known as HSP90 for its molecular weight in the range of 90-kilodaltons. Over the last two decades investigators have explored the use of small molecules to inhibit these important proteins. Among the first compounds to be isolated and applied were derivatives of geldenamycin. Although geldenamycin itself is a poison that causes severe liver damage, its derivative 17-AAG, also known as tanespimycin, has successfully entered clinical trials.

The current studies examined two other HSP90 inhibitors. One retaspimycin, has been developed by Infinity Pharmaceuticals. This clinical trial combined retaspimycin with docetaxel and compared results with docetaxel alone in 226 patients with recurrent lung cancer. None of the patients had received docetaxel prior to the trial. Drugs were administered every three weeks and the efficacy endpoint was survival with a subset analysis focused on those with squamous cell cancer. The trial fell short of its pre-designated endpoint. Interestingly, the study failed to provide benefit even in patients who were specifically targeted by their tumor’s expression of the K-Ras, p53 or by elevated blood levels of HSP90, the putative biomarkers for response.

The second trial examined a different HSP90 inhibitor developed by Synta Pharmaceuticals. The drug ganetespib was combined with docetaxel and the combination was compared with docetaxel alone. The results just reported indicate that the combination provided a median survival of 10.7 months, while docetaxel alone provided a median survival of 7.4 month. Although this represented a three month improvement, it did not meet the pre-specified target.

Taken together, these results could dampen enthusiasm for these agents. This would be unfortunate, for this class of drugs is active in a number of human tumors. We observed favorable activity and synergy for the HSP90 inhibitor geldenamycin and its derivative 17-AAG as we reported (Nagourney RA et al Proc. AACR, 2005). More importantly, 17-AAG (tanespimycin) provided objective responses in 22% and clinical benefit in 59% of patients with recurrent HER2 positive breast cancer after these patients had failed therapy with Herceptin. This clearly supports the role of HSP90 inhibition in breast cancer and would suggest that other more carefully selected target diseases could benefit as well.

The function of HSP90 is not completely understood as it influences the intracellular trafficking of dozens of proteins. One of the complexities of this class of drugs is that they protect and enhance the function of both good and bad proteins. After all, the HSP90 protein doesn’t know which proteins we, as cancer doctors, would like it to protect.

When we apply the EVA-PCD analysis to these and related classes of compounds we focus our attention upon the downstream effects, namely the loss of cell survival. That is, whatever proteins are influenced, the important question remains “did that effect cause the cells to die?” Classes of compounds with nonspecific targets like the HSP90 inhibitors will surely be the most difficult to characterize at a genomic or proteomic level: What protein? What gene?

Functional platforms like the EVA-PCD offer unique opportunities to study these classes of agents. We are convinced that the HSP90 inhibitors have a role in cancer therapy. It would be unfortunate if these setbacks led us to “throw the baby out with the (hot) bathwater,” thus slowing or preventing their use in cancer treatment.

With Cancer, Don’t Ask the Experts

I was recently provided a video link to a December 2013 TEDx conference presentation entitled, “Big Data Meets Cancer” by Neil Hunt, product manager for Netflix. Mr. Hunt’s background has nothing to do with cancer or cancer research. His expertise is in technology, product development, leadership and strategy and has personally shepherded Netflix to its current market dominance. With his background and lack of expertise in cancer, he is an ideal person to examine cancer research from a fresh perspective.

Mr. Hunt begins with a (admittedly) simplistic look at cancer research today. Because he is a data guy, naïve to all of the reasons why cancer cannot be cured, he can look anew at how it might be cured. Using a graphic, he defines cancer as “a long-tail disease” made up of outliers. He points out that most 20th century medical successes have been in the common diseases that fall close to the thick end of the curve. As one moves to the less common illnesses data becomes more scant. Echoing a new conceptual thinking, he points out that cancer is not a single disease but many, possibly thousands.  His concept is to accumulate all of the individual patient data to allow investigators to explore patterns and trends: a bottom up model of cancer biology. Many of his points bear consideration.

For those of you who have read these blogs, you know that I am an adherent to the concept of personalized cancer care. I have articulated repeatedly that cancer patients must be treated as individuals. Each tumor must be profiled using available platforms so that time and resources will not be wasted. We have used the same term “N-of-1” (a clinical trial for one patient) that Mr. Hunt uses in his discussion. He provides two anecdotes regarding patients who benefitted dramatically from unexpected treatment choices. His rallying cry is that contemporary clinical trials are failing. Again, this is an issue that I have addressed many times. He then describes broad-brush clinical protocols as the “tyranny of the average.”

The remainder of the discussion focuses upon possible solutions. Among the obvious hurdles:
1.    Cancer centers are hesitant to share data.
2.    The publication process is slow.
3.    Few are willing to publish negative trials.

To counter these challenges, he points out that small organizations are more incentivized to share and that successes in long-tail diseases can resurrect failed drugs, thereby repaying the costs. Several points were particularly resonant as he pointed out that early adopters face outsized resistance but their perseverance against adversity ultimately evolves the field. He sees this as a win-win-win scenario with patients receiving better care, physicians witnessing better outcomes, and pharmaceutical companies gaining more rapid approval of drugs.

As I watched, it occurred to me that Mr. Hunt was articulating many points that we have raised for over the last decade. As an outsider, he can see, only too clearly, the shortcomings of current methods. His clear perceptions reflect the luxury of distance from the field he is describing. Mr. Hunt’s grasp of cancer research is direct and open-minded. Many problems need fresh eyes. Indeed as we confront problems as complex as cancer it may be best not to ask the experts.

What is Cancer Research?

According to Wikipedia, cancer research is “basic research into cancer in order to identify causes and develop strategies for prevention, diagnosis, treatments and cure.” At face value this seems self-evident, yet “cancer research” means different things to different people.

Most cancer patients think of cancer research as the effort to achieve the best possible outcome for individual patients. Taxpayers and donors to charitable organizations also tend to view the process through the lens of therapeutics. But patient treatment is but a small part of cancer research. One of the largest cancer research organizations, the American Cancer Society, was the subject of an investigative report by Channel 2 in Atlanta, Georgia. They found that this billion dollar organization spent 32% of the money it raised on raising money. What of the other 68%? How much of that money actually goes to patient care? When one factors in education, transportation, administration, PR, salaries and basic research, actual patient care support is close to the bottom of the list.

More instructive is an examination of how people engaged in cancer research define their work. On one side are clinical investigators (trialists) who administer the treatments developed in the laboratories of scientists after pre-clinical analyses. On the other side are the basic researchers whose job it is to answer questions and resolve scientific dilemmas. They are granted enormous amounts of money to delve into the deepest intricacies of cancer biology, genomics, transcriptomic and proteomics in an effort to better understand the etiology (causation) of this dreaded disease.

In examining this disjointed field, I considered my own area of work. I am a clinical investigator who also conducts research in a laboratory. As such, I straddle the fence between basic research and clinical science. This is increasingly dangerous ground, as the gap between scientists and clinicians grows wider by the day. Most clinical investigators have, at best, a passing understanding of molecular biology, and most molecular biologist have absolutely no idea what clinical medicine is. This is unfortunate, for it is the greater blending of science with clinical therapy that will lead to better outcomes. Pondering this dichotomy I recognized that my job is first and foremost to save lives and to alleviate suffering. For me, the laboratory is a means to an end. It is a tool that I use to resolve clinical questions. What drug, what combination, what sequence? These questions are best answered in the laboratory, not in patients, wherever possible.

For the basic scientist the task is to answer a question. For them the laboratory is an end unto itself. They use multiple parameters to examine the same question from different angles, seeking to control every variable. A good scientific paper will use genomic (DNA), transcriptomic (RNA), and proteomic (protein expression) analyses until the issues have all been resolved to their satisfaction. In the literature this is known as “elegant” science. The operative term here is control. The scientist controls the experiment, controls the environment, controls the outcome, and controls the publication process. They are in charge.

What of the poor clinical investigator, who must, per force of necessity, be humble. They are not in control of the clinical environment and rarely understand the intricacies of the metabolic, genomic and proteomic events taking place before their eyes. They must approximate, sometimes guess and then act. For the clinician, the laboratory is an opportunity to answer practical real-world questions, not nuanced theoretical principles.

The greatest criticism that a scientist can level at an opponent is a lack of focus, defined as the inability to drill down onto the essence of the question. These scientists sit on study sections, review manuscripts and fund grants. Over decades they have been allowed to define the best research as the most narrowly focused. Incrementalists have out-stripped, out-funded and out-maneuvered big thinkers. While basic researchers examine which residue on the EGFr domain becomes phosphorylated, clinical physicians must do hand-to-hand combat with the end result of these mutations: non-small cell lung cancer.

Medical history instructs that big questions are best answered when prepared minds (William Withering, Ignaz Semmelweis, etc.) pursue scientific answers to real clinical questions. Unfortunately, today’s clinicians have been relegated to the role of “hypothesis testers.” This has led to a profusion of blind alleys, failed clinical trials and the expenditure of billions of dollars on extremely “interesting questions.”

George Bernard Shaw said, “England and America are two countries separated by a common language.” Increasingly, cancer research has become two distinctly different disciplines divided by a common name.

The Rising Cost of Cancer Research: Is It Necessary?

For anyone engaged in developmental therapeutics and for those patients who need new approaches to their cancers, an editorial in the Journal of Clinical Oncology casts a disturbing light on the field The authors examine the impact of the growing research bureaucracy upon the conduct of clinical trials. They use Thomas Edison, who filed 1,093 U.S. patents, to exemplify successful trial and error research. By inference, they suggest that if Mr. Edison were working today in the modern regulatory environment we would all be reading this blog by candlelight. While much of Edison’s work focused upon household conveniences like light bulbs and phonographs, the principals that underlie discovery work are every bit the same.

Although regulations have been put in place to protect human subjects, the redundancies and rigorous re-reviews have outstripped their utility for the patients in need. The process has become so complex  that it is now necessary for many institutions to use professional organizations to conduct trials that could easily have done in the past by an investigator with a small staff. These clinical research organizations (CRO’s) are under the gun to adhere to an ever growing collection of standards. Thus, every detail of every consent form is pored over sometimes for years. This has had the effect of driving up the cost of research such that the average Phase III clinical trial conducted in the 1990s that cost $3,000 to $5,000 per accrued patient, today costs between $75,000 and $125,000 per patient. Despite this, the safety of individuals is no better protected today than it was 30 years ago when all of this was done easily and cheaply.

While funding for cancer research has increased slowly, the cancer research bureaucracy has exploded. One need only visit any medium to large size hospital or university medical center to witness the expansion of these departments. Are we safer? Do our patients do better? The answer is a resounding “No.” In 2013, according to the authors,  the average patient spent a mere 53 seconds reviewing their consent forms before signing them, while the average parent, signing on behalf of their child, spent only 13 seconds.

The take home messages are several. First, the regulatory process has become too cumbersome. Were this the cost of scientific advance we would accept it as a fact of life, but patients are not safer, trials are not faster and outcomes are not being enhanced. Second, the cancer research process has overwhelmed and undermined cancer researchers. In keeping with Pournelle’s Iron Law of Bureaucracy, “. . . in any bureaucratic organization there will be two kinds of people: those who work to further the actual goals of the organization, and those who work for the organization itself.”Is there anyone who donates to the American Cancer Society who wants their money to go toward more regulation?

The problem is not with the academic physician. Medical scientists want to do studies. Marching alongside are the patients who are desperate to get new treatments. While many criticize the pharmaceutical industry, it is highly unlikely that these companies wouldn’t relish the opportunity to see their drugs enter the market expeditiously. Standing between patients and better clinical outcomes is the research bureaucracy. Should we fail to arrest the explosive growth in regulatory oversight we will approach a time in the near future when no clinical trials will be conducted whatsoever.