The MYC project - The MYC oncoprotein as a target for a novel, specific cancer treatment
Indication: Cancer
Target mechanism: MYV-dependent apoptosis
Founding researchers: Ass. Professor Marie Henriksson
Screening of small molecules
Actar have since 2005 collaboration together with Ass. Professor Marie Henriksson, who is one of Sweden’s most knowledgeable in the MYC signaling pathway and the association of MYC to cancer. Marie Henriksson is docent in tumorbiology and is head of the department of microbiology, Tumor and cellbiology (MTC), Karolinska Institutet. The project is based on results from Henriksson’s laboratory demonstrating that a small molecule could induce apoptosis in cancer cells in a MYC dependent matter. A unique cell system was developed by Henriksson and colleagues 2005 (Patent: WO 2006/0311194A11). The cell system includes human neuroblastoma cells, where MYC experimentally can be regulated from very high, to very low expression levels. The cell system makes it possible to simultaneously screen compounds for activity, cell penetration, and acute toxicity.
Specific aims
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To identify small molecular compounds those selectively inhibit proliferation and/or induce cell death in tumor cells with high MYC expression.
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To test candidate substances in vitro and in vivo for the development of new anticancer therapy.
Scientific Background
The MYC family of proto-oncogenes includes three main evolutionarily conserved genes c-, N- and L-MYC, which encode related proteins. These proteins belong to a large network of transcriptional regulators called the MYC network that plays a key role in the regulation of cell growth, apoptosis and differentiation. The members of the MYC family, c-MYC, MYCN and L-MYC, have been identified as being translocated or overexpressed in many different tumors. These include lymphomas, neuroblastomas (NB) and breast, cervix, colon, head and neck, ovarian and small cell lung carcinomas, among others.
The roles of c-MYC in cell transformation, apoptosis and carcinogenesis have been extensively investigated in the past few years. Inactivation of the strict regulation of MYC protein expression results in uncontrolled cell proliferation. The increased pool of proliferating cells may increase the risk of secondary mutations contributing to tumor development. Mutations in the apoptotic program results in an imbalance between proliferation and cell death with predominance for the former, thereby facilitating MYC-driven tumorigenesis. MYC is activated in a number of different tumors such as small cell lung cancer, breast carcinoma, osteosarcoma, glioblastoma, cervix carcinoma, myeloid leukemia, plasma cell leukemia, Burkitt’s lymphoma and neuroblastoma. Together these data suggest that targeting MYC expression may be an attractive therapeutic modality to be explored for cancer treatment.
Work plan status and methodology
We have screened a chemical library in cells with the inducible MYCN expression in order to identify compounds that specifically can inhibit the proliferative function of MYCN and/or enhance its pro-apoptotic effect. The library contained a ”diversity set" of compounds with a wide range of different structurally small molecules. The substances have been selected on the basis of their low toxicity, low molecular weight and suitability as drugs.
Using the above described strategy we have identified two compound classes that inhibit cell proliferation and/or induce apoptosis in cells with high but not low MYCN expression.
To evaluate the potential effect in vivo, we are currently testing selected compounds in different xenograft models to investigate the effect in the treatment of human NB. The xenograft models allows monitoring of therapeutic effects in vivo and comparison of therapeutic efficacy between different modalities using not only multiple measurements of tumor size (volume and weight) during and after therapy, but also hematotoxicity, hepatotoxicity and response to the therapy analyzed with high resolution magnetic resonance tomography (MR), MR proton spectroscopy (MRS) and quantitative RT-PCR for tyrosine hydroxylase mRNA expression. Moreover, we are also testing the effect of these compounds in combination with standard chemotherapeutic agents. This will allow new ways of potential combination therapy.
Why MYC?
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MYC is among the most frequent deregulated oncogenes in human cancers.
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Long-term or transient inactivation of MYC gene was reported to be associated with cessation of cell growth, enhanced apoptosis and tumor regression.
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MYC is expressed only in cycling cells. These constitute a small minority of the normal population in most organs. Toxicity associated with anti-MYC therapies would be expected to be similar to that associated with other traditional cytotoxic agents.
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Its expression levels are associated with sensitivity to certain chemotherapeutic agents, and thus overexpression and/or inhibition might sensitize cells to traditional chemotherapeutic agents.
Significance of targeting MYC as a basis for development of a novel cancer therapy
The MYC protein is often overexpressed in pediatric tumors such as Burkitt’s lymphoma and NB. Pharmacological inactivation of MYC on gene- or protein level could therefore be a specific and efficient therapy for these MYC-driven tumors. In particular MYCN amplified NB affecting young children provides a therapeutic challenge that today is a significant therapeutic dilemma. Identification of new substances that specifically can block the function of MYC and/or activate the pro-apoptotic effect of MYC could be important both for adjuvant and palliative treatment of these diseases, but also for other tumors since MYC is a universal proliferation factor activated in many malignancies.
References:
Adhikary S, Eilers M. Nat Rev Mol Cell Biol. 2005, 6(8): 635-45.
Lua X, Pearson A, Luneca J. Cancer Letters. 2003, 197:125–130.
Jain M, Arvanitis C, Chu K, Dewey W, Leonhardt E, Trinh M, Sundberg C, Bishop M, Felsher D. Science. 2002, 297: 102-104.