One of Dr. William Osler (1849-1918), widely considered the father of modern medicine and “the greatest diagnostician to ever wield a stethoscope,” said: “Treat the whole patient, not just the disease.” The phrase he used specifically used was: “The good doctor treats the disease; The great physician treats the patient who has the disease.” He also insisted that “it is much more important to know what kind of disease a patient has than what kind of disease a patient has,” thus making the axiomatic statement of Hippocrates that “it is much more important to know which person has the disease than which disease the person has.” Even today these are still vital words for most doctors.
Regardless of the wisdom of these axioms, the editors of the journal Oncologist captured the zeitgeist and struck a chord with the scientific community when they reprinted an article from the Wall Street Journal entitled “New era of personalized medicine: targeted drugs for each individual genetic profile.” ” The premise of this 1999 article, which introduced the catchy moniker “personalized medicine,” is in direct contradiction to what Osler (and Hippocrates) preached, namely caring for individual patients rather than their individual illnesses, as below explained.
By comparison, a few months before this article was published, in September 1998, the FDA approved a monoclonal antibody called Herceptin, or trastuzumab, to treat patients with metastatic breast cancer whose tumors overexpress the HER2 protein. Herceptin has become the poster child for a new gene-based treatment paradigm or model that uses DNA, RNA, receptors or enzymes to guide medical decisions and classify genetically similar patients. A diagnostic test (HercepTest; Dako, Glostrup, Denmark) that stains tumor tissue for the presence of HER2 overexpression was approved concurrently with Herceptin to identify the most likely responders.
The success of Herceptin and the HerceptTest ushered in a new era of what became popularly and scientifically known as “personalized medicine.” A catchy if somewhat inaccurate term: “Personalized medicine” is often misinterpreted by the popular press and sometimes even by scientists and clinicians as meaning a holistic treatment of the person with particular attention to the preferences and interests of the individual patient, which actually does is not the case. Although other, more representative names are now used, including “molecular medicine,” “layered medicine,” “biologically personalized medicine,” “pharmacogenetic medicine,” “individualized medicine,” and “precision medicine,” this also applies to “personalized medicine.” undoubtedly the OG and still the one most talked about in the media and society.
The irony of personalized or precision medicine (PM) is that, contrary to the advice of Hippocrates and Osler, it aims to treat the disease and not the patient based on their genetic profile and any identified genetic alterations. PM essentially pushes other patient-specific factors such as age, gender, family history, social and professional circumstances, psychology, experiences, preferences and lifestyle into the background.
Another irony is that the high-precision therapies may be too precise and well-designed. Under the intense selection pressure of these therapies, diseases are forced to fight their way out of eradication through the evolution of resistance, broadly leading to treatment failure and poorer clinical outcomes. This appears to be a strong argument for using a combination of targeted therapies that work together to block multiple, rather than just one or a few, genes, proteins or pathways. In some cases, such as the anti-HIV triple cocktail, this is the answer to the pervasive problem of drug resistance, but it is usually accompanied by increased and potentially intolerable side effects.
Additionally, these therapies often target normal as well as diseased tissue because the proteins they block are expressed throughout the body and contribute to normal cell function and disease progression. Therefore, common side effects of targeted therapies include skin rash, diarrhea, high blood pressure, skin depigmentation, and thyroid, kidney, and liver damage.
Perhaps unsurprisingly, there has been something of a backlash against personalized medicine after the inflated expectations attached to it early on failed to materialize. This rise and fall in expectations perfectly describes the Gartner hype cycle, which models the fluctuations of events for a new treatment or paradigm as the initial bubble of enthusiasm is pierced by the subsequent needle of reality. This will result in either a period of recovery or continued disillusionment, as shown in the figure below.
Photo credit: EpicentRx
Possible next steps in the development of personalized medicine include therapies that target not specific genes, proteins, or signaling pathways per se, but rather multiple abnormalities that, because they occur almost exclusively in diseased tissues, protect normal tissues from toxicity. Abnormalities common to many diseased tissues include overgrown and poorly constructed blood vessels, reduced oxygen supply, low pH, excessive inflammation, and dysfunctional immune cell behavior.
This sounds more like “personalized medicine” because the patient and his well-being come first and the illnesses from which he suffers come second, even though the two are of course inextricably linked.
Image: Getty Images, Yuuji
Dr. Bryan Oronsky serves as EpicentRx’s Chief Development Officer, combining first-hand clinical experience as a physician with 17 years of pharmaceutical development experience. EpicentRx’s pipeline includes treatments designed to not only reverse resistance to standard therapies such as chemotherapy and checkpoint inhibitors, but also improve their tolerability. The Company’s small molecule, RRx-001, is one of the most advanced direct NLRP3 inflammasome inhibitors in clinical development and has been studied in over 300 multimorbid cancer patients, both alone and in combination with other therapies. RRx-001 has been evaluated in multiple independent studies for diseases in which immune and inflammasome activation contribute to disease pathology. These include cancer, myocardial infarction, pulmonary hypertension, acute kidney injury, acute radiation syndrome (ARS), malaria, multiple sclerosis, Parkinson’s disease and Alzheimer’s disease.