The mission of the CRCC is the support of promising new directions of research into all aspects of cancer, including its origin, prevention and cure. The CRCC provides seed grants to faculty on the ten campuses, with the expectation that the most promising research will thereafter be funded by larger, long-term grants from other agencies. CRCC awards grants to new faculty to initiate cancer research projects, to established investigators in areas of research other than cancer to initiate cancer research projects, and to established investigators to initiate studies in new areas.
Stimuli responsive polymers are an efficient means of targeted therapy. Compared to conventional agents, they increase bioavailability and efficacy. In particular, polymer hydrogel nanoparticles (NPs) can be designed to respond when exposed to a specific environmental stimulus such as pH or temperature. However, targeting a specific metabolite as the trigger for stimuli response could further elevate selectivity and create a new class of bioresponsive materials. In this work we describe an N-isopropylacrylamide (NIPAm) NP that responds to a specific metabolite characteristic of a hypoxic environment found in cancerous tumors. NIPAm NPs were synthesized by copolymerization with an oxamate derivative, a known inhibitor of lactate dehydrogenase (LDH). The oxamate functionalized NPs (OxNP) efficiently sequestered LDH to produce an OxNP-protein complex. When exposed to elevated concentrations of lactic acid, a substrate of LDH and a metabolite characteristic of hypoxic tumor microenvironments, OxNP-LDH complexes swelled (65%). The OxNP-LDH complexes were not responsive to structurally related small molecules. This work demonstrates a proof of concept for tuning NP responsiveness by conjugation with a key protein to target a specific metabolite of disease.
Erythrocyte-derived nano-probes functionalized with antibodies for targeted near infrared fluorescence imaging of cancer cells
Constructs derived from mammalian cells are emerging as a new generation of nano-scale platforms for clinical imaging applications. Herein, we report successful engineering of hybrid nano-structures composed of erythrocyte-derived membranes doped with FDA-approved near infrared (NIR) chromophore, indocyanine green (ICG), and surface-functionalized with antibodies to achieve molecular targeting. We demonstrate that these constructs can be used for targeted imaging of cancer cells in vitro. These erythrocyte-derived optical nano-probes may provide a potential platform for clinical translation, and enable molecular imaging of cancer biomarkers.
Multiple myeloma (MM) is an aggressive hematopoietic cancer of plasma cells. The recent emergence of three effective FDA-approved proteasome-inhibiting drugs, bortezomib (Velcade), carfilzomib (Kyprolis), and ixazomib (Ninlaro) confirms that proteasome inhibitors are therapeutically useful against neoplastic disease, in particular refractory MM and mantle cell lymphoma. This study describes the synthesis, computational affinity assessment, and preclinical evaluation of TIR-199, a natural product-derived syrbactin structural analog. Molecular modeling and simulation suggested TIR-199 covalently binds each of the three catalytic subunits (β1, β2 and β5) and revealed key interaction sites. In vitro and cell culture-based proteasome activity measurements confirmed that TIR-199 inhibits the proteasome in a dose-dependent manner and induces tumor cell death in multiple myeloma and neuroblastoma cells as well as other cancer types in the NCI-60 cell panel. It is particularly effective against kidney cancer cell lines, with more than 250-fold higher anti-tumor activities than observed with the natural product syringolin A (SylA). In vivo studies in mice revealed a maximum tolerated dose (MTD) of TIR-199 at 25 mg/kg. The anti-tumor activity of TIR-199 was confirmed in hollow fiber assays in mice. Adverse drug reaction screens in a kidney panel revealed no off-targets of concern. This is the first study to examine the efficacy of a syrbactin in animals. Taken together, the results suggest that TIR-199 is a potent new proteasome inhibitor with promise for further development into a clinical drug for the treatment of multiple myeloma and other forms of cancer.
Related Research Centers & Groups
- UC Discovery Grant Program; a funding opportunity through UC Research Initiatives (UCRI)
- UC Lab Fees Research Program (LFRP); a funding opportunity through UC Research Initiatives (UCRI)
- Multicampus Research Programs and Initiatives (MRPI); a funding opportunity through UC Research Initiatives (UCRI)
- Proof of Concept Commercialization Gap Grants (PoC); a funding opportunity through UC Research Initiatives (UCRI)
- University of California Research Initiatives (UCRI)