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-1216 is for multiple, therapy resistant or high unmet need solid tumors. HSB-1216 exploits a key feature of certain tumors that rely on an excessive LIP within the cell to modify the dysregulated iron microenvironment of cancer. In our Phase 1 study we intend to test HSB-1216 in a variety of solid tumors. Although we have received orphan drug designation (ODD) in small cell lung cancer for HSB-1216’s active drug, we may pursue ODD in multiple indications. HSB-1216 has the potential to be used in cancer patients who have failed standard-of-care therapies in solid tumors. HSB-1216 is being advanced to alleviate these devastating consequences due to a lack of therapies.

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

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 highly targeted bifunctional inhibitory compound in Quatramer with single digit nanomolar IC50 against PI3K-delta and HDAC6, which is also known to downregulate c-myc, a highly pursued and yet undruggable cancer drug target. The Quatramer platform achieves optimal tumor targeting and bioavailability of the highly potent targeted small molecule. HSB-510’s active drug, in co-development via a Cooperative Research and Development Agreement with the National Center for Advancing Translational Sciences, part of the National Institutes of Health, induced necrosis in several mutant and FLT3-resistant acute myeloid leukemia (AML) cell lines and primary blasts from AML patients, while showing no cytotoxicity against several normal cells. The FLT-3 gene is associated with high risk of relapse and poor clinical outcomes upon treatment with conventional chemotherapy in AML patients. Target specific engagement of PI3K-delta and HDAC6 was further demonstrated using the cellular thermal shift assay. HSB-510 also showed ideal pharmacokinetic properties in mice via intraperitoneal administration which provides a means to examine the biological effects of inhibiting these two enzymes with a single molecule, either in vitro or in vivo.

HSB-114: TNF-alpha DNA 

HSB-114 is a novel immunotherapeutic agent which uses our proprietary Quatramer technology to deliver tumor necrosis factor-alpha (TNF-alpha or TNF-α) gene into cancer cells. Previous immunotherapeutic strategies used adenovector technology requiring replication deficient gene deletions and complex manufacturing controls in order to deliver the TNF-alpha gene, but posed a theoretical risk of systemic toxicity and adjacent tissue damage due to overflow of TNF-alpha in blood from the tumor, resulting in some dose-limiting toxicities. We believe our novel non-viral immunotherapeutic TNF-alpha gene therapy, HSB-114, builds on the previous clinical development program with improved scalability and tunability to treat metastatic soft tissue sarcomas.