Abstract 1647: Novel transcriptional inhibitors for the inhibition of melanoma growth
Authors: Taylor Kylie M. , Alhendi Ahmad MN , Halliday Gary , Prado-Lourenço Lionel 
Published: August 2015

Melanoma is one the most commonly diagnosed cancers in Australia and while treatment is generally successful if the tumor is identified early, once the disease begins to spread the prognosis is considerably worse. The recent approval of new targeted therapies (Vemurafenib, Dabrafenib and Trametinib) has improved progression-free survival for patients carrying the common V600- B-Raf mutations. However even when these inhibitors are used in combination many tumors still develop resistance and furthermore there is a lack of treatment options available for patients who do not carry the mutated form of B-Raf. Therefore there is a pressing need for new therapeutics to address this deficit.

The AP-1 transcription factor family has been shown to play an important role in numerous aspects of melanoma tumorgenesis including cellular proliferation and survival, making these transcription factors attractive targets for new treatments. Therefore, a high throughput screening was performed on several libraries of chemical compounds to identify those capable of inhibiting AP-1 directed transcription in vitro. Two lead compounds (X and BT2) were identified for further testing. From these a number of analogues were produced to modify their activity. Those that showed the most improvement above the leads against several melanoma lines were selected for further testing.

The in vitro activity of these compounds was characterised in detail against two human melanoma cell lines, one wild type for B-Raf and one carrying the common V600E mutation. In 2D culture both compounds inhibit melanoma cell proliferation; induce apoptosis and cell cycle arrest and inhibit clonogenic capacity. These compounds have little cytotoxicity (LDH) and retain their activity for at least a month under a variety of environmental conditions. Furthermore in 3D spheroid assays the compounds show similar levels of activity.

In vivo proof-of-concept testing is underway to assess the compounds activity in immunocompetent (xenograft) and immunocompromised (allograft) model. In parallel, bioinformatics analysis of mass spectrometry, kinome and microarray data is underway to identify the exact mechanism of action and the specificity of these inhibitors.

In summary, the identified compounds show promising anti-melanoma activity in vitro. They inhibit human melanoma growth and clonogenic capacity and induce apoptosis and cell cycle arrest in 2D culture at submicromolar concentrations, comparable to the clinically approved drug Tramatenib. They show little cytotoxicity and also inhibit growth in a 3D spheroid model at submicromolar concentrations. The AP-1 transcription family, in particular c-Jun, have been shown to be important players in the development of melanoma. As such, these compounds may prove to be effective treatments for melanoma irrespective of B-Raf status and warrant further investigation both in vitro and in vivo.

Citation Format: Kylie M. Taylor, Ahmad MN Alhendi, Gary Halliday, Lionel Prado-Lourenço. Novel transcriptional inhibitors for the inhibition of melanoma growth. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1647. doi:10.1158/1538-7445.AM2015-1647