The Human Micro Biome

There is a growing recognition that we as a species, humans that is, are not a single organism but a community of organisms living in synchrony. As scientists have recognized for many years, the human gut, skin, and digestive tract are colonized by trillions of bacteria, fungi and other microbes. What we did not realize until recently, was how important these organisms are to our health and well-being

The microenvironment of the human gastrointestinal tract reflects the interplay between bacteria, our diet, intestinal digestive enzymes, lipids, polysaccharides, amino acids, and the by-products of metabolism. The specific make-up of each individual reflects their environment, diet, and family heritage. Indeed, our bacterial flora are transmitted to us by our mothers, who prior to the advent of pasteurized baby-foods, pre-chewed their infant’s food.

More to the point, we now realize that bacterial infections and exposures to foreign antigens early in life protect and prepare us for a healthy adult life. Many modern maladies, such as asthma, diabetes, hypertension, even possibly autism and schizophrenia, may reflect infections, immune responses and the timing thereof. It has been suggested that infections with parasites modulate our immune response. In our increasingly clean environment, devoid of hookworms, tapeworms, and the like, our overactive immune system creates autoimmunity in the form of rheumatoid arthritis, systemic lupus and other maladies.

This reflects the growing recognition that human biology is in fact human ecology. The importance of this cannot be overstated when we examine human tumor biology. We are continually bombarded by the teachings of a cadre of scientists who believe whole heartedly that they can answer the puzzle of human cancer by examining the intricacies of individual human cancer cells, primarily at the level of DNA.  Nothing could be further from the truth.

Take for example just one of the myriad of signaling pathways. Beta catenin is among the most potent tumor promoters. The deranged function of beta-catenin has been identified in several human tumors including prostate, lung and colon. Its closest association being that with colon cancer, wherein the loss of the APC protein (adenomatous polyposis coli), results in a particularly aggressive form of the disease.  The APC protein normally combines with axin and glycogen synthase kinase 3 beta (GSK3B) which all together function to regulate beta-catenin. It is the loss of APC that releases Beta-catenin and drives polyps to become cancerous.

However, upstream of this triumvirate of regulatory proteins are the integrin-ca cadherin proteins that communicate across the cell membrane. By changing the environment of the colon itself, we can influence the integrins, which regulate the cadherins. This in turn regulates beta catenin.  Thus, colon cancer may not arise from changes in our genetic makeup but instead may be driven by micro-environmental changes in the colonic milieu that alter cellular behavior and drive malignant transformation.

Again and again, we are forced to recognize the complexity of human biology. Now we realize that it is not just the genome to the transcriptome to the proteome, but indeed the micro biome.

Empowering Patients Towards Personalized Cancer Care

We have one more guest blogger to introduce during Dr. Nagourney’s absence: Patricia Merwin. Pat just celebrated her fourth anniversary of wellness after receiving a diagnosis of metastatic lung cancer.

In July of 2011, I attended a local TEDx conference in Long Beach, CA where Dr. Robert Nagourney gave a compelling talk about the nature of his work and the future of cancer care. TED is a global organization with a mission to “share ideas worth spreading,” a very appropriate forum for Dr. Nagourney to share his insights into cancer and how to defeat it.

Just three months earlier, at another TEDx event in the Netherlands, Dave deBronkart also gave a talk about the future of cancer care.  Dave deBronkart, better known as “E-patient Dave,” was diagnosed in January 2007 with a rare and terminal kidney cancer.  Given a dismal prognosis, Dave refused to cede his life to “standard care.”  Instead, he turned to a group of fellow patients online and found the information that eventually led to a treatment that saved his life. Dave deBronkart has since become a prolific online patient advocate and an internationally renowned speaker on the subject of patient empowerment and participatory medicine.

Like e-Patient Dave, I was given a “dismal prognosis” when I was diagnosed in 2008 with advanced metastatic lung cancer.  I too refused to cede my life to the standard protocol of the day. But it was not my health care providers who led me to Dr. Nagourney, it was a close friend.  Empowered with the knowledge that it was possible to improve my odds for survival, I chose functional profile testing (EVA-PCD®) to help determine my personalized treatment plan. It was a wise, informed decision resulting in the best possible outcome.  I have since become an online patient advocate, spreading the word to thousands of other patients so that they can become knowledgeable about this important test that could save their lives.

According to Dr. Nagourney, “Every system performs exactly as it was designed to perform. The current system of medical oncology provides adequate care for the average patient. There is little room for true, individualized care, for it disrupts the norm.”  But every patient with cancer has the same objective. To find the treatment that will work for “me.”  With a system skewed toward averages and away from the individual, the path to personalized medicine must be to empower the person with the most at stake – the patient. Dr. Nagourney says, “Today’s patient must become his or her own best advocate.”

More and more, patients are turning to online forums and other patient groups, not just for support, but to seek and share the latest news and information about treatments, side effects, tests, etc. If two heads are better than one, then thousands of engaged patients should, at the very least, provide good food for thought, “ideas worth spreading.”

Dr. Nagourney believes that “it’s in the online trenches where the real, personal war of cancer is being waged.  The old paradigm, that knowledge runs downhill from academics to practitioners to patients is being turned upside down as empowerment goes from the bottom up, not just from the top down.”  I’m sure e-Patient Dave would agree, along with countless other e-patients like him.

The Good, the Bad and the Good

Two years ago, almost to the day, I met a charming gentleman who had been diagnosed the preceding month with metastatic non small cell lung cancer.

The work-up that confirmed his diagnosis also identified an EGFR mutation. This mutation enabled him to receive the targeted agent erlotinib (Tarceva®) as first line therapy and it provided immediate benefit. An incidental finding in his work-up was a meningioma (a benign brain tumor that often arises in the midline of the brain, in an area known as the falx).

Follow up MRI showed no growth of the meningioma. The patient remained on the same therapy for three months at which time his treating physician decided to consolidate him with chemotherapy. The patient’s tolerance could not have been worse: nausea, malaise, fatigue and a 30 pound weight loss. He requested that I assume his care. After careful consideration, I put him right back on what worked in the first place – erlotinib.

With the exception of a few minor toxicities the patient did beautifully. As we approached his restaging with PET/CT and MRI of the brain, scheduled for August 2012 (his two-year point), he presented to a university medical center with disturbing neurological symptoms. An MRI revealed the meningioma to be much larger than originally found two years earlier. Surgery was scheduled for the following day.

The patient and I discussed his situation by phone as he sat in his hospital room awaiting the surgery. If this were a meningioma, it could be removed. However, if this was related to his lung cancer, then there was an opportunity at hand to determine (using the EVA-PCD® platform) whether the cancer was still responsive to erlotinib or had developed mutations that might confer resistance (e.g., T790M). On the one hand, high dose pulse erlotinib can be effective for CNS disease, so long as resistance has not developed. On the other hand, newer classes of drugs that target T7090M might be required.

We needed tissue for testing, so we could create a functional profile of the tumor, and the surgery was 12 hours away. The patient wanted us to do the study. I wanted to do the study. The problem was that I needed to arrange to get tissue to the lab and time was running short.

With an admirable degree of sleuth work, we identified the surgical resident on duty that evening. We explained our need and he proceeded to explain in great detail that this would never happen. Above and beyond the protocols and standards by which he delivered care, he had 45 other patients to cover, as well as consults to conduct. I hung up disappointed that this opportunity would be missed.

The next morning as I finished hospital rounds I noticed a 6:40 a.m missed call on my cell phone. It was from the hospital where the patient was undergoing surgery. I then received a second call from the same number. It was the attending senior surgeon. He was about to scrub in for the scheduled surgery and offered to assist me in any way he could. He explained that they hoped and believed that this was a benign meningioma. If it was, he would remove it and there would be no need for our involvement. An hour later, communicating via speakerphone in the OR, the surgeon explained that this was indeed adenocarcinoma consistent with the patient’s lung cancer diagnosis. He promised to process the tissue carefully, and then provided his cell phone number so we could communicate. I felt a sense of great relief.

While I cannot say what our laboratory tests will find, the story is both educational and inspirational. The patient is an example of a breakthrough in medical science that provided him an excellent and durable response with comparatively little toxicity. That was the good.

The bad reflected the overworked resident’s insouciance. He was busy, it was late and it appeared that we had confused him with someone who cared. After all, there is no payback to perform above-and-beyond-the-call-of-duty medicine. That was sad, for we are now training physicians who are technicians and not healers. They play by the rules and never extend themselves. No one can ding them for doing their job and no one applauds them for doing more.

The really good news was the response of the attending physician. This individual whom I have never met, evidenced an admirable degree of patient advocacy, commitment and compassion. This patient’s good outcome mattered to him and if there was something that I could bring to the table to help this person in need, then he was all there.

We are at a crossroads in medicine. Will we sponsor the healers or promote the technicians? In our laboratory we do everything in our power to provide all the science that we can bring to bear for every patient. The one component that we cannot offer as a service is the art of medicine. That is up to each individual physician.

Venture Capital Goes Genomic

During the 1960s, 70s and into the 90s, a field of investigation arose that examined buyer’s practices when it came to the consumption of goods and services. Algorithms were developed to interrogate consumer choice. One such treatise was reported in 1994 (Carson, RT et al, Experimental Analysis of Choice, Marketing Letters 1994). What these researchers explored were the motivations and forces that drove consumption. When choices are offered, decisions are driven by such factors as complexity and utility. Complexity demands personal expertise or failing that, input from experts, while utility places a value on the good or service.

A recent report from a small biotechnology company called Foundation Medicine has brought this field of endeavor to mind. It seems that this group will be offering DNA sequencing to select chemotherapy drugs. This service, currently priced at $5,800, will focus upon a small cassette of genes that they described as “key” in tumor growth. Based on their technology they have already raised $33.5 million from the likes of Third Rock, Google and Kleiner Perkins Caulfield & Byers, venture capital sources. The CEO of Foundation substantiates the approach by pointing out that fully 150 people have already used their services. One hundred and fifty!

It seems from this report that our colleagues in the field of molecular profiling have studied the dictates of “Experimental Analysis of Choice” to a “T.” What we have is the perfect storm of medical marketing.

First, the technology is so complex as to be beyond the ken of both patients and physicians alike. Thus, expertise is required and that expertise is provided by those engaged in the field. Second, the utility of drug selection is beyond reproach. Who in their right mind wouldn’t want to receive a drug with a higher likelihood of a response when we consider the toxicities and costs, as well as the consequences of the wrong treatment? Dazzled by the prospect of curative outcomes, patients will, no doubt, be lining up around the block.

But, let’s deconstruct what this report is actually telling us. First, a scientifically interesting technology has been brought to the market. Second, it exists to meet an unmet need. So far, so good. What is lacking, however, is evidence. Not necessarily evidence in the rarefied Cochrane sense of idealized survival curves, nor even Level II evidence, but any evidence at all. Like whirling dervishes, patients and their physicians are drawn into a trancelike state, when terms like NextGen sequencing, SNP analysis and splice variants are bandied about.

Despite the enthusiastic reception by investors, I fear a lack of competent due diligence. To wit, a recent article in Biotechniques, “Will the Real Cancer Cell Please Stand Up,” comes to mind. It seems that cancer cells are not individual entities but networks. A harmonic oscillation develops between tumor, stroma, vasculature and cytokines. In this mix, the cancer cell is but one piece of the puzzle.

Indeed, according to recent work from Baylor, some of the tumor promotion signals in the form of small interfering RNAs, may arise not from the cancer cells, but instead from the surrounding stroma. How then, will even the most punctiliously perfect genomic analyses of a cancer cells play out in the real world of human tumor biology and clinical response prediction? Not very well I fear. But then again such a discussion would require data on the predictive validity of the method, something that appears to be sorely lacking.

Will today’s gene profile companies prove to be the biotech Facebook IPOs of tomorrow?

No One is More Interested in Curing Your Cancer Than You

A diagnosis of cancer thrusts a, heretofore, healthy individual into the strange and unfamiliar territory of medical oncology. Many of my patients describe this transition as “entering the cancer bubble.” Suddenly, you are on the inside and everyone on the outside is talking at you about what to do, where to go, whom to see, and what treatments to receive.

From the inside of the bubble however, all of this has a hollow ring as you ponder many options, few good and some, positively frightening. Unfortunately, few patients have the time to complete a MD, or PhD, between diagnosis and the initiation of treatment. Lacking the requisite expertise, they turn to the “authorities” for advice.

Depending on which “authority” one consults, the recommendations may be colored by prejudices and biases. Some physicians adhere strictly to the National Comprehensive Cancer Network guidelines. Others insist upon accrual to Cooperative Group and Phase II trials. University-based investigators will often recommend developmental studies. And some physicians will follow the path of least resistance, examining such issues as cost, chair time and reimbursement, before considering what treatment to deliver.

It is in this milieu, that patients find themselves adrift. Who exactly should you trust? What is their motivation? To put it crassly, when they recommend a specific treatment, what’s in it for them: Cooperative Group points (provided to the most active accruers), academic accolades (the currency of junior faculty), cost containment (the purview of the managed care physicians), or finally, profit margins? Yes, there are a small number of physicians whose choices reflect their own pecuniary interests.

The antidote to all this uncertainty lies within each patient; answers to vexing questions crying out to be heard. These answers reflect the biologic features of each individual’s tumor. What pathway, what repair mechanism, what survival signal drives your tumor? No one has a perfect answer, not the genomic investigators (despite their protestations to the contrary), nor the immunohistochemists, despite the significant appeal of the platform. And not the immunologist (despite brilliant progress in this field over recent years). The closest approximation to human tumor biology is, well, human tumor biology. Using cellular constructs, in the form of native state microspheroids, we can today approximate the response profiles of patients undergoing systemic therapies. Using systems approaches to complex questions, the multitude of factors that contribute to objective response can be examined and elucidated.

No test is perfect. No patient is guaranteed a good outcome. Yet, doubling the objective response rate, and as we and others have documented, improving the time to progression and overall survival can be achieved with available methodologies that apply functional profiling to individual tumors.

No one would walk away from an investment formula that doubled the value of their portfolio. Few would turn down the opportunity to enhance their real estate positions predicated on reliable information from a realtor. Yet everyday, physicians convince patients to walk away from available, published, established methods that can improve response rates, diminish toxicities and avoid futile care. In this environment it is critical for patients to take charge of their own cancer management. Patients must not be dissuaded from seeking the best possible outcomes. Physicians, no matter how well intentioned, are human. Their opinions can be colored by misconceptions and an incomplete understanding of the questions at hand. Laboratory analysis empowers patients to make smart decisions.

In the game of cancer we need all the help we can get. After all, no one is more interested in saving your life than you.

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.

When 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.

Time for Rational Therapy?

At the 2012 American Association for Cancer Research (AACR) meeting recently held in Chicago, I again observed that the AACR presentations continue to diverge from those at the American Society of Clinical Oncology (ASCO). At this year’s meeting, I’m not sure I heard the word “chemotherapy” a single time. That is, all of the alphabet soup combinations that make up the sessions at ASCO are nowhere to be found at the AACR meeting. Instead, targeted agents, genomics, proteomics and the growing field of metabolomics reign supreme.

Over the coming weeks, I will blog about some of the more interesting presentations I attended. However, I note below several themes that seemed to emerge.

First: That cancer patients are highly unique. In one presentation using phosphoprotein signatures to connect genetic features to phenotypic expression, the investigator conducted 21 phosphoprotein signatures and found 21 different patterns. This, he noted, reflected the “uniqueness” of each individual.

Additional themes included the growing development of meaningfully effective immune therapies. There was evidence of a renewed interest in tissue cultures as the best platform to study drug effects and interactions. Although virtually every presentation began with the obligatory reference to genomic analysis, almost every one of them then doubled back to metabolism as the principal driver of human cancer.

Interestingly, the one phrase that cropped up time and time again was rational therapeutics. Although they did not appear to be referring to our group, it was comforting to note that they are at least, finally coming around to our philosophy.

The Tyranny of Medical Experts

Over the last several years a number of decisions have been handed down from medical experts, I use the term “handed down” advisedly. Like the Olympian Gods or appellate court judges, these dictates are provided to the unsuspecting medical public as fiats. Among these are the roles of mammograms for women under 50 (not recommended), PSA screening for men (not recommended), and a variety of determinations that seem to many counterintuitive. In the past, similar recommendations have been handed down regarding a series of “unnecessary” tests, the cessation of which could save millions of dollars annually.

These topics were the subject of a recent article by Drs. Pamela Hartzband and Jerome Groopman, members of the faculty at Harvard Medical School. Published in the Saturday, March 31, 2012, Wall Street Journal, their article “Rise of the Medical Expertocracy,” focuses on the new paternalism that has come to define “Best Practices” in the healthcare. What most concerns these authors is the transition from physicians as experts, to governmental entities as experts. With this new bureaucracy comes an entirely new industry dedicated to the generation of medical metrics designed to provide doctors and hospitals report cards on their performance. Like evidence-based medicine, yesterday’s catchphrase for improving treatments, “Best Practices” are now being forced upon practitioners.

Where the purveyors of these approaches have gone wrong, is their misguided attempt to apply average treatments to average patients with the expectation of average outcomes. Despite the appeal of simplified treatment algorithms, there are no average patients and it follows that there are no average outcomes.

In a recent presentation at the American Association for Cancer Research meeting held in Chicago March 31 – April 4, 2012, one of the presenters at the melanoma session described whole genome sequencing on 21 human melanomas. To their chagrin they found 21 completely different phosphoprotein signatures. From the macroscopic to the most microscopic mankind in general and his tumors in particular, distinguish themselves for their unique attributes.

The theme of Drs. Hartzband and Groopman’s article echoes loudly in our study of cancer patients. We will only succeed in saving money and saving lives when we stop banging round pegs into square holes and get down to the challenging, but very doable work of matching each individual to their best treatment option – truly personalized medicine.

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 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. 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.

Our 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.”

The Molecular Origins of Lung Cancer

I had the luxury of attending the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; Biology, Therapy and Personalized Medicine held in San Diego earlier this month. I say luxury, for as my schedule closes in on me and I sometimes find myself working 13-hour days, it can be difficult to take even a couple of days away to attend meetings. But this conference was too good to pass up (hats off to Marge Foti and all the AACR staff for all their great work).

This symposium organized by David Carbone and Roy Herbst, brought together a broad spectrum of sophisticated scientists and international investigators, as well as community members and fundraising organizations who had the opportunity to present a special session on patient advocacy.

The meeting began with a keynote address examining microRNAs and lung cancer presented by Frank Slack from Yale University. He examined the growing recognition that lung cancer arises not only from gene mutations but also from small fragments of RNA that can up- or down-regulate normal genes in abnormal ways. This was the topic of discussion for many subsequent presentations.

As an aside, many of the readers will know that I am generally underwhelmed by genomic analyses for the prediction of cancer response. The fact that normal genes can function abnormally under the control of these small RNA sequences is just one more example of the genotype–phenotype dichotomy that cannot be adequately examined on static contemporary genomic platforms.

Many presentations examined the molecular biology of lung cancer with important distinctions being drawn between adenocarcinoma and squamous cell carcinomas. While adenocarcinomas reveal a growing number of targets – EGFR, ALK, ROS, RAS, and others – all the subject of small molecule inhibitors; squamous cell carcinomas provide fewer opportunities for the use of these classes of drugs.

One of the interesting discussions was the frequent mutation of LKB1 in lung cancers. Work going back several years by John Minna, a pioneer in this field, identified changes in this metabolic regulator as a common finding in lung malignancies.

Additional presentations examined chemoprevention, molecular pathology, new mechanisms to categorize lung cancer subtypes, and a very interesting discussion of field cancerization. In a particularly interesting analysis, Ignacio Wistuba from M.D. Anderson, showed that molecular changes in the surface epithelium of the lung bronchioles recapitulated the molecular biology of the final tumor in a step-wise manner, inversely related to the distance to the tumor. That is, starting at the main bronchi, one or two mutational changes were detected. Moving closer to the site of the tumor, additional mutations were accumulated. Finally arriving at the site of the established malignancy, all of the constituent mutations associated with this particular cancer became manifest; a saltatory slide into cancer presumably associated with exposure to carcinogens.

Among the other exciting presentations were updates on redox-based approaches to cancer presented by Kenneth Tew and Garth Powis.

Jeff Engelman presented an update on a new class of agents that target the RAS pathway. This is ongoing work that he and his group have reported on over the last several years. We have been engaged in related work using an MEK/ERK inhibitor similar to the compound that Dr. Englemen reported on at this meeting. It is exciting indeed to see early clinical results with this class of compounds, for we have identified many patients who might benefit from this pathways’ inhibition. We wait with great anticipation for FDA approval of these compounds so that our patients currently being identified as candidates in the laboratory may soon receive these treatments.