Redox Homeostasis, Metabolic Pathways and Plasticity in Uveal Melanoma Compared to Other Cancers.

Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer, accounting for 15–20% of the disease [,,]. TNBC is characterized by the lack (or very low levels) of immunohistochemically detectable estrogen receptor (ER), progesterone receptor (PR), and the lack of amplification of human epidermal growth factor receptor 2 (HER2) []. Due to the lack of these therapeutic targets, TNBC patients do not respond to hormonal or HER2-targeted therapies [] and are prone to disease recurrence and metastasis []. Treatment strategies for TNBC primarily rely on surgery, chemotherapy, and radiation therapy [,]. The therapeutic landscape of TNBC has expanded to include immunotherapies and PARP inhibitors in certain cases [,]. Unfortunately, the effectiveness of chemotherapy for TNBC is undermined by debilitating side effects and rapid emergence of chemo-resistant clones [,]. Despite recent advances, TNBC still has low survival rates, highlighting the need for more effective treatments []. Therefore, it is essential to identify novel molecular targets and inhibitors to improve survival for patients diagnosed with TNBC. Phosphodiesterase 10A (PDE10), a cyclic nucleotide-degrading enzyme that hydrolyzes both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), has been identified as a potential oncoprotein and therapeutic target which is overexpressed in several tumors, including colon, lung, and ovarian cancers, where it promotes cancer cell proliferation and survival by suppressing cAMP/PKA and cGMP/PKG signaling [,,]. Known PDE10 inhibitors and genetic knockdown of were reported to selectively inhibit colon, lung, and ovarian cancer cell proliferation and induce apoptosis. PDE10 inhibitors were also shown to impair migration and invasion in preclinical models, and sensitize tumors to chemotherapy, while mitigating doxorubicin-induced cardiotoxicity [,]. Notably, PDE10 inhibition by small molecules results in dual suppression of key oncogenic driver pathways, Wnt/β-catenin and RAS-mediated MAPK/AKT [,,]. These studies suggest that targeting PDE10 opens a new strategy for treating TNBC. However, the role of PDE10 in TNBC has not been well studied and currently available PDE10 inhibitors that were developed for CNS disorders such as schizophrenia and Huntington’s disease are not suitable for cancer indications due to low systemic bioavailability and side effects including sedation. Piazza and his colleagues have developed and characterized a novel PDE10 inhibitor, ADT-030 [,]. In a recent study, Bandi et al. demonstrated that ADT-030 is a potent antitumor agent for pancreatic ductal adenocarcinoma (PDAC) that acts by a mechanism consistent with known PDE10 inhibitors by increasing cAMP/cGMP levels and activating PKA/PKG to suppress Wnt/β-catenin and RAS-mediated MAPK/AKT signaling []. Oral administration of ADT-030 significantly suppressed tumor growth in mouse models of PDAC without apparent toxicity. Moreover, ADT-030 potentiated the chemotherapeutic activity of gemcitabine plus nab-paclitaxel, a standard-of-care treatment for PDAC []. In another study, Gazi et al. reported durable and robust antitumor activity of ADT-030 in multiple mouse tumor models []. Additionally, ADT-030-mediated tumor growth inhibition was found to be in part immune-dependent, as ADT-030 treatment enhanced anti-PD-1 therapy []. Both studies reported that ADT-030 treatment reduced metastasis and significantly extended survival in mouse tumor models [,]. In this study, through Kaplan–Meier analysis, we find that PDE10 overexpression in TNBC is associated with poor survival. Results from our in vitro experiments show that ADT-030 significantly inhibited TNBC cell growth, mammosphere growth, and colony-forming ability. Our in vivo studies showed that ADT-030 suppressed syngeneic TNBC tumor growth and had an additive anticancer effect when combined with standard-of-care chemotherapy for TNBC, paclitaxel. Overall, our findings suggest that ADT-030 as a monotherapy or in combination with chemotherapy may offer a novel and effective therapeutic strategy for TNBC.