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.

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.