Oncogene-Blocking Therapies: New Insights from Conditional Mouse Tumor Models

Abstract

Identification of oncogene dependent signaling pathways controlling aggressive tumor growth has led to the emergence of a new era of oncogene-blocking therapies, including Herceptin and Gleevec. In the recent years conditional mouse tumor models have been established that allow switching-off the expression of specific oncogenes controlling tumor growth. The results may have two important implications for oncogene-blocking therapies: (i) downregulation of oncogenes, for instance HER2, MYC, RAS, RAF, BCR-ABL or WNT1, usually leads to a rapid tumor remission. However, it was observed that the initial remission was followed by recurrent tumor growth in most studies. Interestingly, different oncogenes controlled tumor growth in the recurrent than in the primary tumors. This could explain the astonishing clinical observation that inhibitors of a broader spectrum of protein kinases (so-called: "dirty inhibitors") may be superior over highly specific substances. Due to their additional "unspecific" inhibition of a broader spectrum of kinases, they may hamper the escape mechanisms by antagonizing also the pathways controlling recurrent tumor growth. (ii) Experiments with cell systems that allow switching-on oncogene expression point to a so far possibly underestimated cancer drug target: the dormant tumor cell. Oncogene expression (for instance: NeuT or RAS) led to a phenomenon named oncogene-induced senescence or dormancy. Dormant cells are unresponsive to mitogenic stimuli. Importantly, such cells are not at all ready to die, but can remain viable for extended periods of time. Recently, dormant tumor cells have been shown to be more resistant to stresses such as hypoxia or exposure to cytostatic drugs. It still is a matter of debate if and under which conditions dormant tumor cells can be "kissed to life". If these cells contribute to carcinogenesis, it will be important to identify substances specifically killing senescent cells. This review will focus on the possible relevance of senescence both as a pre-oncogenic condition and also for therapy.

ERBB2 and TOP2A in Breast Cancer: A Comprehensive Analysis of Gene Amplification, RNA Levels, and Protein Expression and Their Influence on Prognosis and Prediction

“…Identification of reliable prognostic and predictive factors is still one of the largest challenges in oncology (14,19,20,(29)(30)(31)(32) (19,33). From a biological point of view, analysis of protein function would be ideal.…”

Trastuzumab therapy vs tetracycline controlled ERBB2 downregulation: influence on tumour development in an ERBB2-dependent mouse tumour model

“…Besides improvements in the therapy it led to the concept that only a subgroup of tumours is 'ERBB2 dependent' (Weinstein, 2002;Baselga, 2006;Hengstler et al, 2006). This underlines the need to direct trastuzumab only to this subset of tumours whose growth depends on ERBB2 signalling.…”

“…Women whose breast tumours stain 3 þ for ERBB2 (meaning that strong complete membrane staining is seen in more than 10% of tumour cells) are most likely to respond to trastuzumab (Vogel et al, 2002;Mass et al, 2005) (reviewed by Tokunaga et al, 2006). The activity of trastuzumab in breast carcinomas overexpressing ERBB2 has contributed to the concept that certain tumours are 'oncogene dependent' (Weinstein, 2002;Baselga, 2006;Hengstler et al, 2006). This concept suggests that trastuzumab should be used only for the subset of tumours whose growth depends on the oncogenic signal of ERBB2.…”

Small molecules targeting histone H4 as potential therapeutics for chronic myelogenous leukemia

“…K562 cells were suspended to 50 million cells/mL in Matrigel (BD Biosciences), 0.2 mL of which was s.c. injected into the rear left flank of each mouse (6 -8 wk of age). Mice were monitored and tumor sizes were measured daily; tumor volumes were calculated as 0.5  length  (width) 2 . Tumors were staged for 7 to 14 d to enter growth phase.…”