Key Concepts in Glioblastoma Therapy
The term 'oncogene addiction' was initially coined by Dr Bernard Weinstein to describe the phenomenon that some tumours exhibit exquisite dependence on a single oncogenic protein (or pathway) for sustaining growth and proliferation. Such dependence has been convincingly demonstrated in both tissue culture and transgenic mice systems for oncogenic versions of MYC and RAS. Application of this concept to the clinical setting has achieved variable success in some various cancer types, including chronic myelogeneous leukaemia harbouring the BCR-ABL translocation, Erb2 overexpressing breast cancer, and non-small cell lung cancer harbouring a subset of EGFR mutations. A simplistic application of this concept in glioblastoma would involve identification of the critical 'addicted' oncogene followed by the inhibition of such oncogenes. Unfortunately, the actual biology of glioblastoma is far more complex.
To understand this complexity, a careful analysis of the fundamental notion of oncogenic addiction is needed. In some ways, the observation that tumours exhibit dependence on a particular oncogenic pathway at some point in its history is not surprising. However, considering the plethora of dynamic genetic changes that accumulated during cancer progression, it is somewhat counter-intuitive to suspect that any particular pathway would play a prominent role in maintaining cell viability. Moreover, inactivation of the normal counterpart of the addicted oncogenic protein is often tolerated in normal tissue. These observations suggest that the genetic circuitry of the cancer cell have been extensively reprogrammed to result in this 'addicted' state.
The molecular nature of this reprogramming remains poorly understood. Several hypotheses have been put forward. One hypothesis involves the notion of 'genetic streamlining', where genetic instability in cancer cells is thought to mutationally or epigenetically inactivate certain signalling pathways that are operational in a normal cell but not required for growth in the cancer cell. In this 'streamlined' state, the tumour cell becomes hyper-dependent on the oncogene-driven processes. A more generalised form of this explanation involves the notion of synthetic lethality. Two genes are considered synthetically lethal if cells remain viable with inactivation of either gene. Simultaneous inactivation of both genes, on the other hand, results in cell death. It is thought that the cancer cells have accumulated mutations that are synthetically lethal with the absence of critical oncogenes. The main difference between this hypothesis and the 'streamline' hypothesis is that the mutation in the former can result in a gain or loss of function, whereas the later specifically proposes a loss of function. A third hypothesis suggests that oncogenes reprogramme the tumour cell by both pro-survival and pro-apoptotic signalling. With acute inactivation, the pro-survival signalling decayed faster than the pro-apoptotic signalling, resulting in tumour death. This thesis has been coined the 'oncogene shock' hypothesis.
The main reason for revisiting the framework of oncogene addiction is to discuss the mechanism by which the cells can evolve to avoid such addiction. For instance, in the context of synthetic lethality, EGFR inhibition may be cytotoxic to glioblastoma cells only in the appropriate genetic context. Indeed, therapeutic effects of EGFR inhibition were observed only in patients with tumours expressing an oncogenic form of EGFR and an intact phosphatase and tensin homolog (PTEN) tumour suppressor gene. To complicate the matter, recent studies demonstrate that glioblastomas harbour activation of multiple oncogenic receptor tyrosine kinases, such that inactivation of any single oncogene merely diverts signalling through other active oncogenes. In these contexts, it is evident that meaningful therapy will require simultaneous inhibition of multiple oncogenes or identification of the fitting genetic context (Figure 2).
(Enlarge Image)
Figure 2.
Oncogene and non-oncogene addiction.
Concept 2: Oncogene Addiction
The term 'oncogene addiction' was initially coined by Dr Bernard Weinstein to describe the phenomenon that some tumours exhibit exquisite dependence on a single oncogenic protein (or pathway) for sustaining growth and proliferation. Such dependence has been convincingly demonstrated in both tissue culture and transgenic mice systems for oncogenic versions of MYC and RAS. Application of this concept to the clinical setting has achieved variable success in some various cancer types, including chronic myelogeneous leukaemia harbouring the BCR-ABL translocation, Erb2 overexpressing breast cancer, and non-small cell lung cancer harbouring a subset of EGFR mutations. A simplistic application of this concept in glioblastoma would involve identification of the critical 'addicted' oncogene followed by the inhibition of such oncogenes. Unfortunately, the actual biology of glioblastoma is far more complex.
To understand this complexity, a careful analysis of the fundamental notion of oncogenic addiction is needed. In some ways, the observation that tumours exhibit dependence on a particular oncogenic pathway at some point in its history is not surprising. However, considering the plethora of dynamic genetic changes that accumulated during cancer progression, it is somewhat counter-intuitive to suspect that any particular pathway would play a prominent role in maintaining cell viability. Moreover, inactivation of the normal counterpart of the addicted oncogenic protein is often tolerated in normal tissue. These observations suggest that the genetic circuitry of the cancer cell have been extensively reprogrammed to result in this 'addicted' state.
The molecular nature of this reprogramming remains poorly understood. Several hypotheses have been put forward. One hypothesis involves the notion of 'genetic streamlining', where genetic instability in cancer cells is thought to mutationally or epigenetically inactivate certain signalling pathways that are operational in a normal cell but not required for growth in the cancer cell. In this 'streamlined' state, the tumour cell becomes hyper-dependent on the oncogene-driven processes. A more generalised form of this explanation involves the notion of synthetic lethality. Two genes are considered synthetically lethal if cells remain viable with inactivation of either gene. Simultaneous inactivation of both genes, on the other hand, results in cell death. It is thought that the cancer cells have accumulated mutations that are synthetically lethal with the absence of critical oncogenes. The main difference between this hypothesis and the 'streamline' hypothesis is that the mutation in the former can result in a gain or loss of function, whereas the later specifically proposes a loss of function. A third hypothesis suggests that oncogenes reprogramme the tumour cell by both pro-survival and pro-apoptotic signalling. With acute inactivation, the pro-survival signalling decayed faster than the pro-apoptotic signalling, resulting in tumour death. This thesis has been coined the 'oncogene shock' hypothesis.
The main reason for revisiting the framework of oncogene addiction is to discuss the mechanism by which the cells can evolve to avoid such addiction. For instance, in the context of synthetic lethality, EGFR inhibition may be cytotoxic to glioblastoma cells only in the appropriate genetic context. Indeed, therapeutic effects of EGFR inhibition were observed only in patients with tumours expressing an oncogenic form of EGFR and an intact phosphatase and tensin homolog (PTEN) tumour suppressor gene. To complicate the matter, recent studies demonstrate that glioblastomas harbour activation of multiple oncogenic receptor tyrosine kinases, such that inactivation of any single oncogene merely diverts signalling through other active oncogenes. In these contexts, it is evident that meaningful therapy will require simultaneous inhibition of multiple oncogenes or identification of the fitting genetic context (Figure 2).
(Enlarge Image)
Figure 2.
Oncogene and non-oncogene addiction.