Douglas Hanahan, Robert A. Weinberg. Hallmarks of cancer: the next generation. Cell, Volume 144, Issue 5, p646–674, 4 March 2011
The introduction of mechanism-based targeted therapies to treat human cancers has been heralded as one of the fruits of three decades of remarkable progress of research into the mechanisms of cancer pathogenesis. We do not attempt here to enumerate the myriad therapies that are under development or have been introduced of late into the clinic. Instead, we consider how the description of hallmark principles is beginning to inform therapeutic development at present and may increasingly do so in the future.
The rapidly growing armamentarium of targeted therapeutics can be categorized according to their respective effects on one or more hallmark capabilities, as illustrated in the examples presented in Figure 6. Indeed, the observed efficacy of these drugs represents, in each case, a validation of a particular capability: if a capability is truly important for the biology of tumors, then its inhibition should impair tumor growth and progression.
We note that most of the hallmark-targeting cancer drugs developed to date have been deliberately directed toward specific molecular targets that are involved in one way or another in enabling particular capabilities. Such specificity of action has been considered a virtue, as it presents inhibitory activity against a target while having, in principle, relatively fewer off-target effects and thus less nonspecific toxicity. In fact, resulting clinical responses have generally been transitory, being followed by almost-inevitable relapses.
One interpretation of this history, supported by growing experimental evidence, is that each of the core hallmark capabilities is regulated by partially redundant signaling pathways. Consequently, a targeted therapeutic agent inhibiting one key pathway in a tumor may not completely shut off a hallmark capability, allowing some cancer cells to survive with residual function until they or their progeny eventually adapt to the selective pressure imposed by the therapy being applied. Such adaptation, which can be accomplished by mutation, epigenetic reprogramming, or remodeling of the stromal microenvironment, can reestablish the functional capability, permitting renewed tumor growth and clinical relapse. Given that the number of parallel signaling pathways supporting a given hallmark must be limited, it may become possible to target all of these supporting pathways therapeutically, thereby preventing the development of adaptive resistance.
In response to therapy, cancer cells may also reduce their dependence on a particular hallmark capability, becoming more dependent on another; this represents a quite different form of acquired drug resistance. This concept is exemplified by recent discoveries of unexpected responses to antiangiogenic therapies. Some have anticipated that effective inhibition of angiogenesis would render tumors dormant and might even lead to their dissolution.
In certain preclinical models, where potent angiogenesis inhibitors succeed in suppressing this hallmark capability, tumors adapt and shift from a dependence upon continuing angiogenesis to heightening the activity of another instead—invasiveness and metastasis. By invading nearby tissues, initially hypoxic cancer cells evidently gain access to normal, preexisting tissue vasculature. Initial clinical validation of this adaptive/evasive resistance is apparent in the increased invasion and local metastasis seen when human glioblastomas are treated with antiangiogenic therapies. The applicability of this lesson to other human cancers has yet to be established.
Analogous adaptive shifts in dependence on other hallmark traits may also limit efficacy of analogous hallmark-targeting therapies. For example, the deployment of apoptosis-inducing drugs may induce cancer cells to hyperactivate mitogenic signaling, enabling them to compensate for the initial attrition triggered by such treatments. Such considerations suggest that drug development and the design of treatment protocols will benefit from incorporating the concepts of functionally discrete hallmark capabilities and of the multiple biochemical pathways involved in supporting each of them. Thus, in particular, we can envisage that selective cotargeting of multiple core and emerging hallmark capabilities and enabling characteristics (Figure 6) in mechanism-guided combinations will result in more effective and durable therapies for human cancer.
The circuit diagrams of heterotypic interactions between the multiple distinct cell types that assemble and collaborate to produce different forms and progressively malignant stages of cancer are currently rudimentary. In another decade, we anticipate that the signaling circuitry describing the intercommunication between these various cells within tumors will be charted in far greater detail and clarity, eclipsing our current knowledge. And, as before, we continue to foresee cancer research as an increasingly logical science, in which myriad phenotypic complexities are manifestations of a small set of underlying organizing principles.