Anna Bianchi-Smiraglia, PhD

Breast cancer is the leading cancer for incidence and second for mortality, in women in the United States. Metastasis is the primary cause of breast cancer associated mortality and once tumors are able to disseminate a patient’s survival chances decrease precipitously. Recently, our group has unveiled a fundamental connection between GTP metabolism and tumor invasion. GTP biosynthesis at its final steps requires the activity of two key enzymes (IMPDH1/2 and GMPS) to convert the purine precursor IMP into GMP. A functional antagonist (GMPR) converts GMP back into IMP. High levels of IMPDH2/GMPS and low levels of GMPR are associated with poor survival in breast cancer patients, especially those with triple negative breast cancer (TNBC, the deadliest subtype, which has higher rates of recurrence and metastasis). Our group has a long history of studying the effects of GTP levels manipulations in multiple cancer systems. Most recently we have identified the rate-limiting enzyme for GTP production, inosine monophosphate dehydrogenase, as a key player in the resistance to doxorubicin in TNBC. IMPDH2 levels modulate response to therapy in naïve cells and are highly upregulated in resistant models. Paradoxically, while sustaining the chemo-resistant phenotype, high IMPDH2/GTP become a novel metabolic vulnerability for these cells and can be exploited therapeutically.

The aryl hydrocarbon receptor (AhR) is slowly emerging as a key metabolic reprogrammer in several tumor types, alone and in collaboration with members of the MYC family of transcription factors. AhR has also a prominent role in the immune system, where its activation can lead to an immune-suppressive and tumor-promoting environment. Our recent work has revealed that AhR can be directly induced by chemotherapy and its antagonism in cancer cells can lead to induction of interferon type I cytokines. Unpublished results from the lab have revealed AhR as a novel regulator of GTP metabolism, a classical MYC target.In neuroblastoma. AhR is still quite an understudied entity and its relationship with MycN, a known driver of the disease, is poorly understood. Our published work strongly supports a tumor promoting role of AhR in neuroblastoma through both regulation of MycN-dependent and -independent signaling as well metabolic reprogramming, as well as through interference with retinoic acid induction of differentiation.

Our efforts are currently focused on understanding the impact of AhR and IMPDH2 antagonism in preclinical models of chemo-resistant TNBC and neuroblastoma, with the long-term goal of empowering the design of novel anti-tumor therapies.