HSB-1216: Novel Inducer of Iron-Mediated Cell Death

Iron is a central player in cancer progression and metastasis and dysregulated in tumors. Certain cancer cells rely on an increased labile iron pool (LIP) which fosters tumor growth, metastasis and relapse. HSB-1216 (Hillstream’s lead compound) normalizes the LIP in tumors and causes cell death by de-linking cancer’s addiction to iron. HSB-1216, is a novel and potent inducer of a powerful mechanism involving iron-mediated cell death.  This process which sequesters iron in lysosomes allows HSB-1216 to cause lysosomal membrane permeabilization of hard-to-treat cancer cells – causing them to rupture and stop replicating.  An area of interest for the development of HSB-1216 are rare cancers with high unmet need.

HSB-888: Novel Inducer of Iron-Mediated Cell Death + Ultra Low-Dose Anthracycline

Sarcomas tumors are mesenchymal in nature and capable of forming in connective tissue, blood, lymphatic and vessels, believed to also effect bone and soft tissue. Sarcomas are rare and account for 1% of cancers – yet encompass about 13% of cases under the age of 20. Most common in bone are osteosarcoma and Ewing’s sarcoma, while those arising from soft tissue are commonly rhabdomyosarcomas. Other sarcomas, such as desmoplastic small round cell and synovial sarcoma are more common into adolescence and young adulthood.

The components of HSB-888 are two anticancer drugs with distinct and complementary mechanisms of actions which together constitute an active combination for treating sarcomas. Hillstream investigated whether the efficacy of this combination could be improved by controlling drug ratios following in vitro and vivo administration. The combinations were evaluated systematically for drug ratio-dependent synergy in vitro using multiple tumor cell lines. In vitro screening informatics on drug ratio-dependent cytotoxicity identified a consistently antagonistic region between payloads at various molar ratios, which also showed multiple synergistic ratios, dependent on the chemical characteristics of either DNA intercalating payload combined with an inducer of iron-mediated cell death.

Co-formulations of these two agents were developed that maintained a fixed drug ratio for stability and release profiling over broad timelines. Drug ratio-dependent antitumor activity was demonstrated in vitro and in vivo for these ratios and improved antitumor activity was observed for a specific molar ratio of DNA intercalator:inducer of iron-mediated cell death (designated HSB-888) compared to drug cocktails in models tested. HSB-888, is a fixed-ratio formulation of DNA intercalator:inducer of iron-mediated cell death, and a lead near-clinical candidate for development in multiple sarcomas.

HSB-510: Novel Bi-Functional Inhibitor for Solid Tumors & Leukemias

HSB-510 is a novel Quatramer based small molecule dual inhibitor of HDAC6-PI3Kδ for the treatment of rare cancers, including acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL). Studies have shown that by disrupting multiple compensatory cyto-protective pathways, HDAC6-PI3Kδ dual inhibitor might have potential therapeutic value. HSB-510 is a Quatramer encapsulated HDAC6-PI3Kδ dual inhibitor with an ideal pharmacokinetic profile and nanomolar potency.

HSB-114: TNF-alpha DNA 

HSB-114 is a next generation immunotherapeutic agent of a previously developed predecessor compound. Quatramer technology allows a proprietary TNF-alpha cDNA to be incorporated preferentially into tumor nuclei, hijacking the cancer’s genome and tricking its machinery to make the powerful cytokine and destroy itself.  HSB-114 can be injected intratumorally or given systemically for metastatic soft tissue sarcoma (mSTS).