3p21.3 Tumor Suppressors, TUSC2/FUS1 Mechanisms of Action and Synergies in Drug Combination Applications
Multiple tumor suppressors were identified in the human chromosome 3p21.3 region where allele losses and genetic alterations occur early and frequently for many human cancers. Tumor Suppressor Candidate 2 (TUSC2), also known as Fusion Protein 1 (FUS1), was found to be the most potent inducer of cancer cell apoptosis among the 3p21.3 tumor suppressors. Recurrent loss of heterozygosity in the 3p21.3 chromosomal region, as well as homozygous deletions and epigenetic inactivation of this area, are observed in early stages of lung, breast, ovarian, liver, cervical, and other cancers suggesting a critical role for multiple genes such as CACNA2D2, PL6, 101F6, TUSC2 (FUS1), BLU, RASSF1, NPRL2, HYAL2, and HYAL1 that reside in 3p21.3.
Research shows that TUSC2 is associated with the early onset of cancer and is highly associated with lung, breast, ovarian, liver, malignant mesothelioma and other cancers. For example, TUSC2 protein is absent or reduced in more than 80% of non-small cell lung cancers and 100% of small-cell lung cancers. Oncoprex incorporates TUSC2 in systemically delivered nanovesicles to target cancer at the molecular level. TUSC2 is a novel pan-kinase inhibitor identified in a chromosomal region where allele losses and genetic alterations occur early and frequently for many human cancers. TUSC2 induces apoptosis (programmed cell death) and controls cell signaling and inflammation. It mediates apoptosis in cancer cells but not normal cells by upregulation of the Apaf-1 dependent apoptotic pathway.
TUSC2 is also useful in connection with Tyrosine Kinase Inhibitors (TKIs) in cancer therapy. TKIs are important regulators of intracellular signal-transduction pathways. They control essential cellular functions, including cell differentiation, cell proliferation, cell survival, transcription, cell cycle progression, apoptosis, cell motility, and cell invasion. Somatic mutations and other genetic alterations result in TKIs deregulating their kinase activity, interrupt TKI signaling, lead to malignant transformation, and are associated with a significant fraction of human cancers. Since experimental and clinical studies have shown that TKI activation by somatic mutation or chromosomal alteration is a common mechanism in a variety of human cancers (including lung cancer), several pharmacological and biological approaches have been developed to specifically block activated EGFR for cancer therapy. TUSC2 acts as a pan-kinase inhibitor with studies showing that Oncoprex works synergistically with erlotinib and gefitinib in both EGFR mutation positive and EGFR mutation negative cancers. Previously conducted preclinical studies have shown synergistic anti-cancer activity when Oncoprex is combined with any of a variety of targeted therapies and chemotherapies, exceeding the anticancer effect of any one drug alone.
Tyrosine kinase inhibitors represent a significant and growing sector of cancer drugs. Some TKI drugs target patients with epidermal growth factor receptor EGFR abnormalities or mutations. Examples are erlotinib (Tarceva®, a registered trademark of the Roche Group and Astellas Pharma) and gefitinib (IRESSA®, a registered trademark of AstraZeneca). Many patients benefit from EGFR TKI therapies; however, the majority of cancer patients do not benefit as EGFR TKI drugs generally work only in the fraction of patients with the EGFR mutation.
Oncoprex™ Enhances Effect of Platinum Drugs
Oncoprex also increases antitumor activities of platinum based chemotherapy drugs. Combination of Oncoprex and cisplatin results in a 4- to 6-fold increase over the anticancer activity of cisplatin alone in NSCLC cancer indicating that TUSC2 acts to sensitize NSCLC cells to platinum drugs. The effect of TUSC2 on chemosensitivity was associated with down-regulation of MDM2, accumulation of p53, and activation of the Apaf-1 apoptotic pathway.
Based upon preclinical studies including animal models expressing human cancers with EGFR mutation positive and EGFR wildtype cancers, the combination treatment of Oncoprex and either erlotinib or gefitinib provided synergistic tumor cell killing to overcome drug-induced resistance by simultaneously inactivating the EGFR and the AKT signaling pathways and by inducing apoptosis in resistant cells with wildtype EGFR.
These findings indicate that intravenous Oncoprex can overcome TKI induced or intrinsic therapeutic resistance to TKIs to provide synergistic cancer growth inhibition and pro-apoptotic effects to more effectively treat cancer patients.
Accordingly, the company is directing initial commercial development toward combination treatment regimens using Oncoprex with currently marketed EGFR TKI drugs, and is planning to conduct a phase II clinical trial using Oncoprex in combination with erlotinib. The FDA approved protocol enrollment criteria includes advanced NSCLC patients without an activating EGFR mutation (prior chemo) and advanced NSCLC with an activating EGFR mutation who have progressed on erlotinib, providing multiple opportunities to clinically confirm the utility of the Oncoprex + erlotinib combination in either or both EGFR patient groups. Most patients without an activating EGFR mutation cannot benefit from erlotinib. Erlotinib benefits many patients with an EGFR mutation, however most erlotinib patients eventually become resistant to erlotinib therapy. Pre- and post-treatment biopsies from each patient will be analyzed for prognostic biomarkers.