Widening the Path to Personalized Medicine (2011)

Modern medicine is rapidly evolving, driven by the emergence of insights at the crossroads of discovery, development, application, and dissemination sciences.1,2 Discovery is accelerating, fueled by technologies, including “omics,” cell-based therapies, systems biology, and informatics that provide unanticipated insights into molecular pathophysiology. Integration of these technologies is establishing an essential paradigm for identifying mechanisms underlying physiological circuits which are corrupted in disease states. In turn, identification of these processes offers previously unrecognized perspectives resulting in personalized diagnostics and therapeutics in the form of markers of disease prognosis, clinical predictors of therapeutic responses, and molecular markers that optimize management paradigms for patients and populations.1,3–5 Continued resolution of physiological circuits and decoding of molecular programs at the core of disease pathogenesis will form the framework to individualize diagnostic and therapeutic approaches that provide evidence-based patient care solutions.1,3,4,6,7 Unfortunately, while discovery science accelerates exponentially, delivery of its benefits to patients and populations lags.7,8 Hundreds of genetic variants for disease have been identified, yet few have been translated into evidence-based public health guidelines.9–11 This gap in translation is underscored by the availability of more than 1,200 tests for greater than 1,000 different diseases to help diagnose and treat patients, but fewer than 20% of physicians using these tests.12 Similarly, only 5% of highly promising basic science discoveries are ultimately licensed for clinical use, and only 1% are actually used for the licensed indication.10,13 These examples highlight apparent limitations in translating knowledge generated by the new biology, impeding applications for disease control and prevention in patients and populations.1–5,7,8 Paradoxically, limitations in translating the products of discovery into paradigms to manage patients may reflect the overarching strategy of personalized medicine. The goal of personalized medicine is to precisely match the right drug at the right dose to the specific biology of the disease to maximize therapeutic efficacy while minimizing adverse and off-target effects.5,14,15 This approach is anchored by a paradigm in which molecular mechanisms underlying disease pathogenesis are encoded by inherited or acquired genomic variants which produce biomolecular circuits with deviant functions. In turn, the paradigm presumes that these abnormal circuits can be precisely targeted with small molecules or biologics that repair or abrogate the deviant function, or eliminate the cells harboring the errant circuits. Nowhere is this strategy of personalized medicine more evident than in oncology, in which mechanistic insights into the pathophysiology underlying transformation has yielded a rich catalogue of new, previously unrecognized, druggable targets. In turn, these mechanistic targets have become the substrate for a new array of diagnostics and therapeutics, precisely directed with molecular precision to the corrupted circuits that underlie the disease process. While the expectation was that these targeted approaches would provide molecular solutions to the therapy of cancer, what has emerged is a somewhat different picture. For example, in some cases tumorigenesis in breast is associated with overexpression of Her2, an epidermal growth factor receptor (EGFR) family member.16 In turn, overexpression of Her2 drives proliferation and survival of tumor cells which, in part, define the tumorigenic phenotype. In that context, mechanism-based personalized therapy for breast cancer involves ascertaining tumor overexpression of Her2, and in those qualified tumors, treatment in a targeted fashion with herceptin, a humanized monoclonal antibody directed against Her2 which blocks ligand stimulation and activation of downstream oncogenic signaling circuits.16 However, while Her2 is a viable target in breast cancer, it is expressed by only approximately 30% of tumors.16 Further, 70% of patients with HER2-expressing tumors do not respond to treatment.17,18 Moreover, resistance is developed rapidly by treatment in virtually all patients.17,18 Similarly, cetuximab and panitumumab are monoclonal antibodies directed against EGFR which also blocks ligand binding, receptor activation, and stimulation of downstream oncogenic cascades.19,20 In approximately 75% of cases, colon tumorigenesis is associated with amplification of EGFR expression, producing overstimulation of oncogenic circuits mediated by the small GTP binding protein KRAS, which drives neoplastic progression. Here, again, mechanism-based individualized treatment for metastatic colon cancer involves ascertaining tumor expression of wild type KRAS (~60%),20 and in appropriate tumors, targeted treatment with cetuximab and panitumumab which blocks ligand stimulation of KRAS-mediated downstream oncogenic signaling cascades. These agents improve outcomes in patients with metastatic colon cancer. However, they are effective in only approximately 40% of tumors, including those which express that receptor in the context of wild type KRAS.20 Also, only, approximately 30% of patients with wild type KRAS respond to these agents.19,20 Additionally, they produce only small improvements (1–2 months) in progression-free and overall survival. Moreover, ultimately, tumors develop resistance to these targeted agents.19,20 These examples highlight key challenges specifically associated with individualizing approaches to cancer therapy based on molecular mechanisms, including population segmentation, variable responses, limitations in efficacy, and universal induction of resistance. Enabling technologies have revealed the rich molecular heterogeneity of tumors arising from any single organ site. Analyses of multidimensional data arrays employing the tools of systems biology suggest that tumorigensis involves the progressive corruption of genetic, epigenetic, postgenetic (small noncoding RNAs), proteomic and metabolomic circuits, to name a few, with near-infinite complexity. This systems complexity creates a unique mechanistic fingerprint for each patient’s tumor. If we achieve an envisioned future of mapping the molecular mechanisms underlying tumorigensis in each patient, individualization will require a proliferation and diversification of therapeutic approaches that can only be applied to small segments of the diseased population. It is unclear whether there is sufficient capacity and innovation in the biopharmaceutical drug development apparatus to achieve this individualization. Moreover, segmenting the population to individual patient-specific therapies may create a value proposition that is unsustainable in the current profit-driven drug development model. A corollary of this mechanistic diversity is the infinite capacity for tumors to evolve. One hallmark of tumorigenesis is the corruption of normal DNA-damage sensing and repair mechanisms, associated with compromise of apoptotic cascades that would normally inactivate a damaged cell. These mechanistic hallmarks create an almost limitless capability to adapt, through mutation, to environmental challenges, including chemo- and radiotherapy. In that context, individualizing therapeutic approaches by targeting key corrupted oncogenic signaling pathways to which the tumor have become “addicted”21 provides an evolutionary pressure conferring a selective survival advantage to tumor cells that can mutationally adapt. It is this infinite capacity to adapt that contributes to the characteristic variable response rate, quantitatively small therapeutic responses and the inevitable development of resistance that characterizes the activity of most individualized molecular cancer therapies. How do we incorporate these early lessons to maximize the utility of this revolution in therapeutic individualization based on molecular insights? First, it is imperative that in addition to targeting the cure of established tumors, strategies for cancer control must include disease prevention. Attacking established tumors, which have developed the capacity for infinite adaptation and evolution associated with therapeutic evasion, is daunting, with relatively few examples of curative success. Rather, identifying neoplasia at the earliest stages, before invasion and metastasis, and before the evolution of their full mutational capabilities, when developing tumors are maximally sensitive to surgical, pharmacological, radiological, and immunological approaches, continues to be one preferred approach to permanent disease control. Beyond prevention, the personalization of cancer therapy can take an important lesson from the field of infectious diseases. Introduction of antimicrobial therapy early in the 20th century revealed the capacity of infectious agents to develop therapeutic resistance, reflecting their genomic flexibility potentiated by short replication cycles. In that context, administration of antimicrobials represented the application of evolutionary pressure to which infectious agents could readily respond, resulting in the selection of organisms resistant to treatment. As the toolbox of antimicrobials targeting different molecular mechanisms expanded, a clinical strategy evolved that included treating serious infections with multiple antimicrobials. The presumption underlying this strategy suggested that while organisms could develop mutational resistance to a single agent, it was a considerably greater evolutionary challenge to develop resistance to multiple agents attacking diversified mechanisms. Indeed, this approach has been adapted in cancer therapy using nontargeted agents, for example antimetabolites. Emergence of molecular therapies targeting corrupted circuits provides a unique opportunity to attack the biology of tumors at the level of essential programs underlying cellular transformation, and the diversity of cellular components including tumor-perpetuating stem cells. Moreover, multimodality approaches provide a unique opportunity for synthetic lethality, in which targeted agents eliminate molecular pathways on which tumor cells become addicted because of corruption of redundant and overlapping pathways.22 This is exemplified by the utility of poly ADP ribose polymerase (PARP) inhibitors, which prevent repair of damaged DNA, in tumors harboring mutations in BRCA1, also a key regulator of DNA damage repair. Therapeutic individualization attempts to advance treatment paradigms from a population-based approach where on size fits all, to a personalized model where the intervention is precisely matched to mechanistic characteristics defining the pathophysiology specific to each patient. As in any therapeutic strategy, the advantages of this personalized approach, including mechanistic and therapeutic specificity, also confer canonical liabilities including population segmentation, limited efficacy, and universal resistance. Thus, emergent treatment modalities might benefit from broadening the current critical focus on individualized therapeutics, incorporating a return to mutually compatible population-based paradigms. Here, rather than specific molecular characteristics defining tumors in individual patients, the focus could shift to those features that universally characterize tumors in all patients. This one-size-fits-all approach, while mechanistically and philosophically in contradistinction to the revolution in individualized therapy, potentially offers complementary solutions, including therapeutic inclusiveness across the population and broad efficacy. These considerations suggest that, beyond molecular mechanisms that distinguish tumors in individual patients, future research strategies should explore (patho)physiological elements that are common to all patients across the population, to maximize the applicability and efficacy of the resulting druggable targets. We have been set on a path for disease management created by the emerging revolution in science and technology, where pathophysiological processes will be resolved by tailored molecular solutions. Indeed, this emerging approach has already yielded improvements in clinical outcomes in patients with cancer. However, it is essential to continually reevaluate this path and its direction to ensure that advances are maximized for the benefit of patients and populations.