Gee (G719X) Whiz: Novel Mutations and Response to Targeted Therapies

In a recent online forum a patient described her experience using Tarceva as a therapy for an EGFR mutation negative lung cancer. For those of you familiar with the literature you will know that Lynch and Paez both described the sensitizing mutations that allow patients with certain adenocarcinoma to respond beautifully to the small molecule inhibitors.  The majority of these mutations are found in Exon 19 and Exon 21, within the EGFR domain. Response rates for the EGFR-TKI (gefitinib and erlotinib) clearly favor mutation positive patients. Depending upon the study, mutation positive patients have response rates from 53 – 100 percent, generally around 70 percent, while mutation negative response patients have a response rate of 0 – 25 percent, generally about 10 percent.

So why don’t all the mutation positive patients respond and conversely why do some mutation negative patients respond?

The story outlined in this online forum gives some insight. The individual in question carried a rare, and only recently recognized, Exon 18 mutation known as a G719X. This uncommon form of mutation had previously been unknown and few laboratories knew to test for it. Nonetheless, G719X positive patients respond to erlotinib and related agents. Indeed, there may be reason to believe that the more potent irreversible EGFR/HER2 dual inhibitor HKI-272, may be even more selective for this point mutation.

The excellent and durable response described by this individual, would not have been possible had the patient’s first physician followed the rules. That is, had her physician refused to give erlotinib to an (putatively) EGFR mutation negative patient she might well not be here to tell her story. More to the point, her good response (a clinical observation) led to the next level of investigation, namely the identification of this specific EGFR variant

The lessons from this experience are numerous. The first is that cancer biology is complex and, to paraphrase E.O. Wilson, was not put on earth for us to necessarily figure it out. The second, is that molecular biologists can only seek and identify that which they know about apriori.  To wit, if you don’t know about it (G719X) and you don’t have a test for it, and you don’t know to look for it, then it’s a virtual certainty that you aren’t going to find it.

The premise of our work at Rational Therapeutics is that the observation of a biological signal identifies a candidate for therapy whether we understand or recognize the target. Crizotinib was originally developed as a clinical therapy for patients who carried the CMET mutation. Serendipity led to the recognition that the responding subpopulation was actually carrying a heretofore-unrecognized ALK gene rearrangement. Sorafenib was originally evaluated for the treatment of BRAF mutation positive diseases. Yet it was the drug’s cross-reactivity with the VGEF tyrosine kinases that lead to its broad clinical applications. Each of these phenomena represents accidental successes. Were it not for the clinical observation of response in patients, the investigators conducting these trials would have been unlikely to make the discoveries that today provide such good clinical responses in others.

To put it quite simply, these patients and their disease entities educated the molecular biologists.

When we first identified lung cancer as a target for gefitinib, and began to administer the closely related erlotinib to lung cancer patients, neither Lynch nor Paez had identified the sensitizing EGFR mutations. That had absolutely no impact upon the excellent responses that we observed. It didn’t matter why it worked, but that it worked.  While the EGFR story has now been well-described, might we not use functional analytical platforms (functional profiling) to gain insights into the next, and the next generation of drugs and therapies that target pathways like MEK, ERK, SHH, FGFR, PI3K, etc., etc., etc. . . .

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.

American Association of Cancer Research 2012

In my last blog, I described my recent attendance at the American Association of Cancer Research (AACR) meeting held in Chicago. This is the premier cancer research convention for basic and translational research. The AACR was the original cancer research organization that pre-dated its sister organization – the American Society of Clinical Oncology. The focus of the AACR meeting is basic research and the presentations are often geared toward PhD level scientific discovery. I find this meeting the most informative for it provides insights into therapy options that may not arrive in the clinical arena for many years.

Among the presentations was a discussion of NextGen genomic analysis allowing an entire human genome to be sequenced within 24 hours. Mapping genetic elements has enabled investigators at the University of Pennsylvania to explore acute leukemia patients at diagnosis and at the time of recurrence. Based upon mutation analysis, different subsets of patients are observed. Mono and Oligo-clonal populations yield new subpopulations following cytoreductive therapy, wherein a small percentage of tumor cells survive and repopulate as the dominant clone.

The NextGen genomic analysis serves as the basis for new solid tumor studies in which breast biopsies are obtained, before and after therapy with aromatase inhibitors, to examine the clonality of the surviving populations.

William R. Sellers, MD, vice president of Novartis Institutes for BioMedical Research Oncology, described a high throughput robotic technology capable of conducting tens of thousands of combinatorial mixtures to determine drug interactions. What I found most interesting was the observation by this investigator that, “Cell culture remains the most effective means of testing drug combinations.” We agree wholeheartedly.

New classes of lymphoma therapies are in development that target B cell signaling pathways. A prototypic agent being Ibrutinib, the Bruton’s tyrosine kinase inhibitor.

Additional developments are examining SYC as a target for small molecule inhibitors.
Our growing understanding of immune regulation is enabling investigators like James Allison to trigger tumor specific immunity. Agents like ipilumimab (AntiCTLA4), combined with other classes of small molecules and/or antibodies directed toward CD28, PD1, and ICOS regulation have the potential to change the landscape in diseases that extend from melanoma to prostate and breast.

The meeting had innumerable sessions and symposia that were geared toward or touched upon the field of metabolomics. As cells jockey for survival they both up- and down-regulate pathways essential to not only energy production but to the biosynthesis of critical metabolic intermediates. The regulation of PKM2 (pyruvate kinase isoenzyme) is now recognized as a pivotal point in the cell’s determination of catabolism (energy production), over anabolism (biosynthesis), with Serine concentrations playing an important regulatory role.

The PI3K pathway is an area of rapidly growing interest as new compounds target this key regulatory protein complex. Both selective and non-selective (pan PI3K) inhibitors are in clinical testing. Paul Workman’s group was honored for their seminal work in this and related areas of drug development. We reported our findings on the dual PI3K/mTOR inhibitor BEZ235 (Nagourney, RA et al Proc AACR, 2586, 2012).

The double-edged sword of immune response was deftly covered by Dr. Coussens who described the profound tumor stimulatory effects of T-cell, B-cell and Macrophage infiltration into the tumor microenvironment. Small molecules now in development that down-regulate macrophage signaling may soon show promise alone or in combination with other classes of drugs.

The RAS/RAF pathway becomes ever more complex as we begin to unravel the feedback loops that respond to small molecule inhibitors like Erlotinib or Vemurafanib. Investigators like Dr. Neal Rosen from Memorial Sloan-Kettering Cancer Center have long argued that simple inhibition at one node in a cascade of signaling pathways will absolutely change the dynamic and redirect up and down stream signals that ultimately overcome inhibition. Strategies to control these “resistance” mechanisms are being developed. Once again we find that simple genomic analyses underestimate the complexity of human systems.

Among the regulatory topics at this year’s meeting was a special symposium on the development and testing of multiple novel (non-FDA approved) compounds in the clinical trial setting. There will need to be a new level of cooperation and communication forged between academia, regulatory entities and the pharmaceutical industry if we are to move this process forward. I am encouraged by the early evidence that all three are recognizing and responding to that reality.

The themes of this year’s meeting included:
1. A renewed focus on the biochemistry of metabolism
2. Clear progress in field of tumor immunology
3. The growing recognition that human tumors exist as microenvironments and not isolated single cells.

We are particularly gratified by the last point.

Our EVA/PCD focus on human tumor aggregates (microspheroids) isolated directly from patients as the most accurate models for chemotherapy selection and drug discovery appears to be gaining support.

A New Target in Breast Cancer Therapy

In many ways the era of targeted therapy began with the recognition that breast cancers expressed estrogen receptors, the original work identified the presence of estrogen receptors by radioimmunoassay. Tumors positive for ER tended to be less aggressive and appear to favor bone sites when they metastasized. Subsequently, drugs capable of blocking the effects of estrogen at the estrogen receptor were developed.  Tamoxifen competes with estrogen at the level of the receptor. This drug became a mainstay with ER positive tumors and continues to be used today, decades after it was first synthesized.

Recognizing that some patients develop resistance to Tamoxifen, additional classes of drugs were developed that reduced the circulating levels of estrogen by inhibiting the enzyme aromatase, this enzyme found in adipose tissue, converts steroid precursors to estrogen.  Despite the benefits of these classes of drugs known as SERMS (selective receptor modulators), many patients break through hormonal therapies and require cytotoxic chemotherapy.

With the identification of HER-2 amplification, a new subclass of breast cancers driven by a mutation in the growth factor family provided yet a new avenue of therapy – trastuzumab (Herceptin). For HER-2 positive breast cancers Herceptin has dramatically changed the landscape. Providing synergy with chemotherapy this monoclonal antibody has also been applied in the adjuvant setting offering survival advantage in those patients with the targeted mutation.

Reports from the San Antonio breast symposium held in Texas last December, provide two new findings.

The first is a clinical trial testing the efficacy of pertuzumab. This novel monoclonal antibody functions by preventing dimerization of HER-2 (The target of Herceptin) with the other members of the human epidermal growth factor family HER-1, HER-3 and HER-4. In so doing, the cross talk between receptors is abrogated and downstream signaling in squelched.

The second important finding regards the use of everolimus. This small molecule derivative of rapamycin blocks cellular signaling through the mTOR pathway. Combining everolimus with the aromatase inhibitor exemestane, improved time to progression.

While these two classes of drugs are different, the most interesting aspect of both reports reflects the downstream pathways that they target. Pertuzumab inhibits signaling at the PI3K pathway, upstream from mTOR. Everolimus blocks mTOR itself, thus both drugs are influencing cell signaling that channel through metabolic pathways PI3K is the membrane signal from insulin, while mTOR is an intermediate in the same pathway. Thus, these are in truest sense of the word, breakthroughs in metabolomics.

Faster than the Speed of Light

Last week, scientists at CERN, the European particle physics laboratory located outside Geneva, Switzerland, conducted an experiment, the results of which now challenge one of the most fundamental principles of modern physics. I speak of Albert Einstein’s 1905 declaration that the speed of light is an absolute and that nothing in the universe could travel faster.

E = MC2, the principle under which nuclear energy and weapons have been developed, as well as all of the corollaries of the theory of relativity were called into question when a series of sub atomic particles, known as neutrinos traveled from Switzerland to Italy at a speed that was 1/60 of a billionth of a second faster than the speed of light. What has followed has been a flurry of interest by departments of physics all over the world. Confronted with this new finding, these investigators will diligently seek to reproduce or refute the findings.

This was not the first time that someone challenged the primacy of Einstein’s 1905 theory. Indeed, during the 1930s, for largely political and anti-Semitic reasons, the Nazi party attempted to disprove Einstein. Yet, all of the political meanderings, personal vendettas and intellectual jealousy could not unseat Einstein’s guiding principle. That is, until objective evidence in the form of the CERN experiments came to the fore.

Science — however lofty — and scientists — however highly regarded — dwell in the same realm as all the rest of us mere mortals. Their biases and preconceived notions often cloud their vision. Comfortable with a given paradigm, they hold unyieldingly to its principles until they are forced, however unwillingly, to relinquish their belief systems in favor of a new understanding. I write of this in the context of laboratory-based therapeutics – a field of scientific investigation that has provided firm evidence of predictive validity. These technologies have improved response, time to progression and survival for patients with leukemia, ovarian, breast and lung cancers, as well as melanoma and other advanced malignancies. Thousands of peer-reviewed published experiences have established the merit of human tumor primary cultures for the prediction of response. Investigations into the newest classes of targeted therapies are providing new insights into their use and combinatorial potential.

Yet,  while the physicists of the world will now rise to the challenge of data, the medical oncologists and their academic counterparts refuse to accept the unimpeachable evidence that supports  the validity of assay-directed therapy. Perhaps if our patients were treated at CERN in Geneva,  their good outcomes would receive the attention they so richly deserve.

Is Rationed or Rational Medical Care In Our Future?

We are witness to a sea change in medicine. Doctors and nurses are being replaced by “healthcare providers;” medical judgment is being phased out in favor of therapeutic algorithms; and the considered selection of treatments is giving way to rigid therapy guidelines. All the while, the regulatory environment increasingly precludes the use of “off label” drugs. It is understandable why insurers, governmental entities and hospital chains might welcome these changes. After all, once therapies have been reduced to standardized formulae, one can predict costs, resource allocations and financial exposures to the twentieth decimal place. For many medical conditions, these approaches will provide adequate care for the majority of patients.

But, what of the outliers? What of those complicated disease entities like cancer, whose complexity and variability challenge even the best minds? How do we bang the round peg of cancer therapy into the square hole of formulaic care?

There are several answers. The first is the least attractive: In this scenario, predicated upon cancer’s incidence in an older population, at the end or beyond their productive (and reproductive) years, we simply don’t allocate resources. Most civilized modern societies haven’t the stomach for such draconian measures and will seek less blunt instruments.

The second is a middle of the road approach. In this scenario, standardized guidelines that provide the same treatment to every patient with a given diagnosis are developed. Every medical oncologist knows the drill: FOLFOX for every colon cancer, Cytoxan plus Docetaxel for every breast cancer and carboplatin plus paclitaxel for ovarian cancer. The treatments work adequately well, the schedules are well established, the toxicities are well known and no one is cured. The beauty of this approach is that the average patient has an average outcome with the average treatment. By encompassing these regimens into standardized algorithms, we may soon be able to eliminate physicians entirely — first, with nurse practitioners and physician’s assistants and, ultimately, with computers. What is perhaps most surprising about this scenario has been the willingness of the medical oncology community to embrace it, a sort of professional self-induced extinction. At the time of this writing, this is the predominant model and is becoming increasingly entrenched under the auspices of NCCN and related guidelines. The operative term being guidelines, in as much as these “guidelines” are rapidly becoming “dictates.”

The final approach, and the one I find most appealing, is that which utilizes the clinical, scientific, laboratory and technical acumen of the physician to the maximum. Combining diagnostic skill with scientific insight, the physician becomes the captain of the ship, who must assume control from the autopilot once the vessel has entered the tempest and use his/her experience and training to guide the patient to a soft landing. This requires the capacity to think and demands an up-to-date knowledge of many disciplines. The judicious application of laboratory-directed approaches can further enhance the skillset, introducing objective data that is then used to guide drug and treatment selections. Predicated upon an understanding of the patient’s tumor biology, cancer therapy becomes an intellectual exercise that draws upon literature, and a knowledge of pharmacology and physiology. Adding the wealth of newly developed signal inhibitors to the mix only enhances the odds of a good outcome.

This approach improves responses and eliminates futile care. It provides patients the opportunity to participate in their own management. Correctly delivered, it would make available to every patient any FDA-approved drug. While it would seem to some that this would open the floodgates of drug use, I would strenuously disagree. It would instead limit drug administration to those patients most likely to respond, a goal currently pursed by virtually every major institution, yet accomplished by none. While a handful of targeted approaches have come to fruition in the last few years — erlotinib for EGFR mutation, and sunitinib in kidney cancers — most of the molecular profiling being done today doesn’t aid in the selection of therapy but instead provides negative information (e.g. RAS in colon cancer, ERCC1 over expression in lung) enjoining the physician against the use of a given agent but then leaving the unfortunate patient to fend for themselves amidst a panoply of randomly chosen options.

This is the approach that I have chosen to adopt in my own care of cancer patients. Our rapidly growing successes in ovarian, breast, lung, melanoma, leukemias and other diseases could and should serve as a model for others.

The False Economy of Genomic Analyses

We are witness to a revolution in cancer therapeutics. Targeted therapies, named for their capacity to target specific tumor related features, are being developed and marketed at a rapid pace. Yet with an objective response rate of 10 percent (Von Hoff et al JCO, Nov 2011) reported for a gene array/IHC platform that attempted to select drugs for individual patients we have a long way to go before these tests will have meaningful clinical applications.

So, let’s examine the more established, accurate and validated methodologies currently in use for patients with advanced non-small cell lung cancer. I speak of patients with EGFR mutations for which erlotinib (Tarceva®) is an approved therapy and those with ALK gene rearrangements for which the drug crizotinib (Xalkori®) has recently been approved.

The incidence of ALK gene rearrangement within patients with non-small cell lung cancer is in the range of 2–4 percent, while EGFR mutations are found in approximately 15 percent. These are largely mutually exclusive events. So, let’s do a “back of the napkin” analysis and cost out these tests in a real life scenario.

One hundred patients are diagnosed with non-small cell lung cancer.
•    Their physicians order ALK gene rearrangement     $1,500
•    And EGFR mutation analysis     $1,900
•    The costs associated $1,500 + $1,900 x 100 people =    $340,000
Remember, that only 4 percent will be positive for ALK and 15 percent positive for EGFR. And that about 80 percent of the ALK positive patients respond to crizotinib and about 70 percent of the EGFR positive patients respond to erlotinib.

So, let’s do the math.

We get three crizotinib responses and 11 erlotinib responses: 3 + 11 = 14 responders.
Resulting in a cost per correctly identified patient =     $24,285

Now, let’s compare this with an ex-vivo analysis of programmed cell death.

Remember, the Rational Therapeutics panel of 16+ drugs and combinations tests both cytotoxic drugs and targeted therapies. In our soon to be published lung cancer study, the overall response rate was 65 percent. So what does the EVA/PCD approach cost?

Again one hundred patients are diagnosed with non-small cell lung cancer.
•    Their physicians order an EVA-PCD analysis    $4,000
•    The costs associated: $4,000 x 100 people =    $400,000
•    With 65 percent of patients responding, this
constitutes a cost per correctly identified patient =     $6,154

Thus, we are one quarter the cost and capable of testing eight times as many options. More to the point, this analysis, however crude, reflects only the costs of selecting drugs and not the costs of administering drugs. While, each of those patients selected for therapy using the molecular profiles will receive an extraordinarily expensive drug, many of the patients who enjoy prolonged benefit using EVA/PCD receive comparatively inexpensive chemotherapeutics.

Furthermore, those patients who test negative for ALK and EGFR are left to the same guesswork that, to date has provided responses in the range of 30 percent and survivals in the range of 12 months.

While the logic of this argument seems to have escaped many, it is interesting to note how quickly organizations like ASCO have embraced the expensive and comparatively inefficient tests. Yet ASCO has continued to argue against our more cost-effective and broad-based techniques.

No wonder we call our group Rational Therapeutics.

The TEDx Experience

On Saturday July 16, I had the opportunity to present at the TEDxSoCal conference held here in Long Beach. The overall theme for this event was “thriving,” and appropriately, I presented in the afternoon session called, “well-being.” My lecture was entitled “The Future of Cancer Research Lies Behind Us.”

I chose this topic in light of the growing recognition that genomic analyses are not providing the therapeutic insights that our patients so desperately need. As I have written before in this blog, the Duke University lung cancer gene program, which has received much attention recently, is emblematic of the hubris associated with contemporary genomic analytic platforms.

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

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

Many attendees stopped me after my lecture to thank and congratulate me for my presentation. Fearing that my topic might have been too esoteric, I was delighted by the reception and more convinced than ever that there are many enlightened individuals who thirst for new approaches to cancer treatment. It is these people who will forge the next generation of therapy.

American Association of Cancer Research (AACR) Meeting 2011

The Sunday, April 3, 2011, experimental and molecular therapeutics session at the AACR 102nd annual meeting included our presentation on signal transduction inhibitors. Using MEK/ERK and PI3K-MTOR inhibitors we explored the activities, synergies and possible clinical utilities of these novel compounds.

The findings were instructive. First, we saw a good signal for both compounds utilizing the Ex-vivo Analysis of Programmed Cell Death (EVA-PCD) platform. Second, we saw disease-specific activity for both compounds. For the MEK/ERK inhibitor, melanoma appeared to be a favored clinical target. This is highly consistent with our expectation. After all, many melanomas carry mutations in the BRAF gene, and BRAF signals downstream to MEK/ERK. By blocking MEK/ERK, it appeared that we blocked a pathway fundamental to melanoma progression. Indeed, MEK/ERK inhibitors are currently under investigation for melanoma.

For PI3K inhibitors, the highest activity was observed in uterine cancers. This is interest, because uterine carcinomas are often associated with a mutation in the PTEN gene. PTEN is a phosphatase tumor suppressor that functions to block activation of the PI3K pathway. Thus, mutations in the tumor suppressor unleash PI3K signaling, driving tumors to grow and metastasize. Blocking PI3K provided a strong signal, indicating that this approach may be very active in tumors associated with these oncogenic events.

The third point of interest in our report was, perhaps, its most important. Specifically, that we can explore those diseases where MEK-ERK, PI3K and mTOR signaling are less established targets. Cancers of the lung, ovary, colon or breast all manifested profiles of interest. When we combined both pathway inhibitors in a process we call horizontal inhibition, renal cell carcinoma popped up as the best target. These results, though exploratory, suggest a superior approach for drug development, allowing us to identify important leads much faster than the clinical trial process.

Targeted Therapies — The Next Chapter

Within this blog, we have intermittently reviewed the concept of targeted therapies. To reiterate, these are classes of drugs that target specific pathways considered tumorigenic. Among the pathways initially targeted were the epidermal growth factor receptor and the closely related HER2. Shortly after the introduction of EGFr and HER2 directed therapies came the development of drugs that target another critical pathway, mTOR.

Hundreds of compounds are now under development intended to more accurately hone in on the pathways of interest in patients’ tumors. Regrettably, the medical community continues to apply old clinical trial methods to this newest era of drugs. While the selective application of drugs like: Tarceva for EGFR mutants, Herceptin for HER2 over-expressers, and Crizotinib for EML4-ALK mutants, are much more effective in patients with these gene expressions, these are a select few examples of linear thinking that bore fruit.

That is, this gene is associated with this disease state and can be treated with this drug.

Many, if not most cancers will prove to be demonstrably more complicated. Genomic trials can only succeed if we first know the gene of interest and second know that its (over) expression alone is pathogenetic for the disease entity. Even meeting these conditions is likely to result in comparatively brief partial responses due to the crosstalk, redundancy and complexity of human tumor signaling pathways — the “targets” of these new drugs.

To address these complexities, functional analytic platforms that examine outcomes, not targets, are needed. This bottom-up approach has now enabled my team to explore the activity of novel compounds. When investigators develop interesting “small molecules,” we examine the disease specificity, combinatorial potential and sequence dependence of these compounds in short-term cultures to provide meaningful insights that can then be addressed on genomic and proteomic platforms. This reduces the time required to take these new agents from bench to bedside. We cannot solve tomorrow’s questions using yesterday’s mindsets