DHODH is the only member of the seven enzymes involved in de novo pyrimidine synthesis pathway that is located in the inner mitochondrial membrane. DHODH is the fourth enzymatic step in the pathway that converts dihydroorotate to orotate and as part of this reaction, it passes an electron to ubiquinone converting it to ubiquinol, a component of the electron transport chain. Therefore, DHODH is a unique enzyme that links the synthesis of pyrimidines with the manufacture of ATP in the mitochondrial electron transport chain (Khutornenko et. al., 2010, Khutornenko et. al., 2014).

Recent publications have shown that DHODH is a key driver of tumour cell proliferation and survival, in several cancer types.

Acute Myeloid Leukemia (AML)
In AML, researchers at Harvard University (Sykes et. al., 2016) have demonstrated DHODH inhibition leads to differentiation of AML blast cells.  In collaboration with Cancer Science Institute of Singapore, ASLAN003 has demonstrated excellent differentiation of AML blast cells and ASLAN is progressing to phase 2 clinical studies in this indication.

Triple Negative Breast Cancer (TNBC)
In TNBC, Harvard Medical School and University of Melbourne (Brown et. al., 2017) have demonstrated that treatment of Triple Negative Breast Cancer (TNBC) with topoisomerase inhibitors led to a large increase in the intracellular pyrimidine pool via DHODH mediated de novo synthesis of pyrimidines.  The investigators have demonstrated that this huge increase in the nucleotide pool in TNBC tumours after topoisomerase treatment effectively sensitises this cancer to cell specific killing induced by DHODH inhibition.

PTEN Mutated Tumours
PTEN is a tumour suppressor that is commonly mutated in a large percentage of all tumour types.  A 2017 publication by Mount Sinai researchers (Mathur et. al., 2017) has demonstrated that PTEN mutation in several tumour types resulted in preferential channelling of glutamine into the de novo pyrimidine synthesis pathway.  This large increase in the pyrimidine pool facilitates tumour proliferation and therefore highly sensitises PTEN mutated tumours to inhibition by DHODH inhibitors such as ASLAN003.  The vulnerability of PTEN mutated tumours to DHODH inhibition identifies a substantial number of tumour types that will benefit from treatment with ASLAN003.

Asia Prevalent Cancers
ASLAN has worked with world class investigators to generate novel biological data in patient-derived xenografts demonstrating that the combination of ASLAN003 with agents that target DNA damage is highly effective at specifically killing tumour cells in cancer subsets that are highly prevalent in Asia.

References
Brown et. al., 2017. Adaptive Reprogramming of De Novo Pyrimidine Synthesis Is a Metabolic Vulnerability in Triple-Negative Breast Cancer. Cancer Discovery; 7(4); 1-9.

Khutornenko et. al., 2010. Pyrimidine biosynthesis links mitochondrial respiration to the p53 pathway. PNAS, 107(29), 12828–12833.

Khutornenko et. al., 2014. The Role of Dihydroorotate Dehydrogenase in Apoptosis Induction in Response to Inhibition of the Mitochondrial Respiratory Chain Complex III. Acta Naturae, 6(1), 69-75.

Mathur et. al., 2017. PTEN regulates glutamine flux to pyrimidine synthesis and sensitivity to dihydroorotate dehydrogenase inhibition. Cancer Discovery, 7(4), 380-390.

Sykes et. al., 2016. Inhibition of Dihydroorotate Dehydrogenase Overcomes Differentiation Blockade in Acute Myeloid Leukemia. Cell, 167, 1-16.