Beneath the complexity and idiopathy of every cancer lies a limited number of 'mission critical' events that have propelled the tumour cell and its progeny into uncontrolled expansion and invasion One of these is deregulated cell proliferation, which, together with the obligate compensatory suppression of apoptosis needed to support it, provides a minimal 'platform' necessary to support further neoplastic progression Adroit targeting of these critical events should have potent and specific therapeutic consequences

Proliferation, cell cycle and apoptosis in cancer

The RAS proteins control signalling pathways that are key regulators of several aspects of normal cell growth and malignant transformation. They are aberrant in most human tumours due to activating mutations in the RAS genes themselves or to alterations in upstream or downstream signalling components. Rational therapies that target the RAS pathways might inhibit tumour growth, survival and spread. Several of these new therapeutic agents are showing promise in the clinic and many more are being developed.

Targeting RAS signalling pathways in cancer therapy

Gene therapy has a history of controversy. Encouraging results are starting to emerge from the clinic, but questions are still being asked about the safety of this new molecular medicine. With the development of a leukaemia-like syndrome in two of the small number of patients that have been cured of a disease by gene therapy, it is timely to contemplate how far this technology has come, and how far it still has to go.

Progress and problems with the use of viral vectors for gene therapy

The RB and p53 pathways in cancer

The p53 tumor suppressor acts to integrate multiple stress signals into a series of diverse antiproliferative responses. One of the most important p53 functions is its ability to activate apoptosis, and disruption of this process can promote tumor progression and chemoresistance. p53 apparently promotes apoptosis through transcription-dependent and -independent mechanisms that act in concert to ensure that the cell death program proceeds efficiently. Moreover, the apoptotic activity of p53 is tightly controlled, and is influenced by a series of quantitative and qualitative events that influence the outcome of p53 activation. Interestingly, other p53 family members can also promote apoptosis, either in parallel or in concert with p53. Although incomplete, our current understanding of p53 illustrates how apoptosis can be integrated into a larger tumor suppressor network controlled by different signals, environmental factors, and cell type. Understanding this network in more detail will provide insights into cancer and other diseases, and will identify strategies to improve their therapeutic treatment.

Control of apoptosis by p53.

https://www.cell.com/cell/pdf/S0092-8674(00)00123-9.pdf

Opposing Effects of Ras on p53: Transcriptional Activation of mdm2 and Induction of p19ARF

The adenovirus mutant dl1520 (ONYX-015) does not express the E1B-55K protein that binds and inactivates p53 This virus replicates in tumor cells with mutant p53, but not in normal cells with functional p53 Although intra-tumoral injection of dl1520 shows promising responses in patients with solid tumors, previous in vitro studies have not established a close correlation between p53 status and dl1520 replication Here we identify loss of p14ARF as a mechanism that allows dl1520 replication in tumor cells retaining wild-type p53 We demonstrate that the re-introduction of p14ARF into tumor cells with wild-type p53 suppresses replication of dl1520 in a p53-dependent manner Our study supports the therapeutic use of dl1520 in tumors with lesions within the p53 pathway other than mutation of p53

Loss of p14ARF in tumor cells facilitates replication of the adenovirus mutant dl1520 (ONYX-015)

Advances in our understanding of the molecular basis of cancer and the availability of technology to genetically engineer viruses have led to the development of replication-competent viruses to treat cancer. In theory, replication-selective viruses offer several appealing properties as biological agents for cancer therapy: they kill tumor cells selectively, and their replication leads to amplification of their oncolytic potential. Most preclinical experiments in tissue culture and in animal models support this notion. Clinical data on the first generation of replication-selective viruses are now rapidly accruing. The therapeutic index, and ultimately the clinical outcome, will depend on a complex balance between host and viral factors. This review discusses strategies to kill cancer cells based on our understanding of their molecular defects and the progress being made using replication-competent viruses for tumor therapy. We focus our discussion on a replication-selective adenovirus called ONYX-015 that has recently demonstrated encouraging results in clinical trials

Replication-selective viruses for cancer therapy

The basic helix-loop-helix transcription factors myogenin and Id2 mediate specific induction of caveolin-3 gene expression during embryonic development.

Stefan Ries

Papers

Opposing Effects of Ras on p53: Transcriptional Activation of mdm2 and Induction of p19ARF

Loss of p14ARF in tumor cells facilitates replication of the adenovirus mutant dl1520 (ONYX-015)

Replication-selective viruses for cancer therapy

The basic helix-loop-helix transcription factors myogenin and Id2 mediate specific induction of caveolin-3 gene expression during embryonic development.

Oncolytic viruses for the treatment of cancer: current strategies and clinical trials.