ASLAN002 is a potent small molecule inhibitor of RON (IC50 = 1.8nM) and cMET (IC50 = 3.9nM) receptor tyrosine kinases. The Phase 1 study of ASLAN002 showed that it was well tolerated. The Phase 1 data also demonstrated that inhibition of RON resulted in suppression of plasma C-terminal telopeptide (CTX) levels, an established biomarker of osteoclast activity and therefore of RON inhibition. Bristol-Myers Squibb has reacquired the rights to ASLAN002 (BMS777607) and is responsible for all development and commercialisation activities.
ASLAN002 has the potential for synergistic efficacy in combining with anti-PD1 therapies.
RON has three primary roles:
RON (Recepteur d’Origine Nantais/ MSTR1) is a receptor tyrosine kinase closely related to cMET but with highly differentiated biology that is central in control of the macrophage population and enhancement of host immune surveillance. In addition, RON activation in tumour cells promotes aggressive disease, early metastasis and preferential metastasis to bone and bone loss via upregulation of osteoclast function (Kretschmann et al, 2010).
The ligand for RON is macrophage stimulatory protein (MSP also known as Hepatocyte Growth Factor-Like protein [HGFL]) and the biological significance RON kinase inhibition via ASLAN002 has recently been characterised by collaboration between Bristol-Myers Squibb, ASLAN and Professor Alana Welm, University of Utah Huntsman Cancer Institute, USA. Professor Welm has demonstrated that knockout of RON in a metastatic breast cancer model resulted in upregulation of TNFα in circulating macrophages which then led to an increase in tumour specific cytotoxic T-cells that reduced tumour metastasis to the lung. This data was also repeated by inhibiting RON kinase with ASLAN002, which led to an increase in the proportion of TNFαs expressing via CD1b+ macrophage cells and an anti-metastatic response that was dependant on tumour specific CD8+ T-cells.
In peer reviewed publications, Professor Welm has also demonstrated that ASLAN002 can clear tumour metastasis in mouse breast cancer models and that ASLAN002 increases the levels of proinflammatory macrophage and cytotoxic killer T-cells.
RON is overexpressed in a range of solid tumour types but is not normally amplified or mutated (Kretschmann et al, 2010). Approximately 73% of gastric/gastroesophageal cancers overexpress RON/MSP and RON ‘high’ patients have substantially worse overall survival with a median 14 vs. >80 months (Catenacci et al, 2011). Similarly, RON/ MSP high tumours are present in approximately 50% of breast and lung cancers (NSCLC). 16% of cholangiocarcinoma are RON/cMET ‘high’ and again these patients have a much worse overall and disease free survival (Yao et. al., 2013, Watanabi et. al., 2015). When activated, RON can heterodimerise with cMET and EGFR (Yao et al, 2013, Chang et al, 2015) and this has been proposed as the reason why cMET selective inhibitors have shown poor efficacy in cancer types tested to date. RON stimulation on the tumour surface activates the PI3 kinase pathway and upregulates expression of the G:T mismatch specific thymidine glycosylase MBD4. Upregulation of MBD4 results in numerous altered hypomethylated and hypermethylated sites and this epigenetic change to the genomic DNA is associated with poor clinical outcome (Cunha et al, 2014). al, 2014).
ASLAN partnered with Bristol-Myers Squibb (BMS) for the development of ASLAN002. In August 2016, BMS acquired the rights to ASLAN002 in China, Australia, Korea, Taiwan and other Asian territories. BMS is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail against serious diseases. To learn more about BMS, please visit www.bms.com.