Molecular Cancer Therapeutics最新文献

Multiple myeloma is a plasma cell malignancy that is susceptible to drugs targeting protein homeostasis such as thalidomide analogs and proteasome inhibitors. Thalidomide analogs modulate the activity of DDB1/CUL4 E3-ligase complexes to perturb substrate recognition and proteasomal degradation thereof. We hypothesized that the cellular pool of DDB1/CUL4-associated factors (DCAF) may mediate other essential plasma cell processes and offer new targets for therapeutic intervention. Unbiased genetic screening identified DCAF1 (also known as viral protein R-binding protein) as essential for myeloma cell survival with a multidomain structure, offering several distinct opportunities for drug development. Utilizing B32B3, a previously disclosed DCAF1 kinase inhibitor as a template, we developed a series of analogs with enhanced antimyeloma potency. As antimyeloma activity did not associate with dephosphorylation of known DCAF1 kinase substrates, we correlated drug-induced cellular phenotypes with whole-genome CRISPR/Cas9 resistance screening to further define mechanistic activity. These studies identified B32B3 analogs as microtubular destabilizing agents with potential DCAF1 kinase-independent properties and in vivo efficacy in multiple myeloma and lymphoma.

Stimulator of IFN genes (STING) is an innate immune pathway that activates a type I IFN response upon detection of intracellular DNA from foreign pathogens as well as tumor cells. STING signaling is critical for antiviral immunity and can be co-opted to drive an antitumor immune response. However, STING activation requires careful and controlled agonism to drive immune activation in the tumor microenvironment (TME) while avoiding toxic systemic immune activation. Indeed, nontargeted small-molecule STING agonist therapeutics have shown limited antitumor activity in the clinic, likely due to their short half-life and poor retention within the TME. We hypothesized that targeted delivery of a potent STING agonist payload directly to the TME via an antibody-drug conjugate (ADC) may overcome some of these limitations. In this study, we report the development of a novel STING agonist ADC with a noncleavable linker-payload (ncSTING). Tumor-targeted ADCs employing this linker-payload (ncSTING ADC) elicited robust antitumor activity in a variety of preclinical murine tumor models. We found that Fcγ receptor binding affected antitumor activity as ADCs with a wild-type Fc drove more antitumor activity than ADCs with an Fcγ receptor-binding mutant Fc in a subset of tumor models. Moreover, tumor-targeted ncSTING ADCs elicited tumor regression with reduced systemic immune activation compared with the systemic administration of the released payload. Altogether, these data provide a therapeutic rationale for the targeted delivery of a potent STING agonist payload via an ADC.

T-cell engager (TCE) immunotherapy has demonstrated significant clinical activity in multiple cancers by inducing coengagement of T cells and tumor cells, resulting in T-cell activation and T cell-dependent cellular cytotoxicity (TDCC) against tumor cells. Current-generation TCEs are predominantly composed of antibody-based binding domains targeting the cluster of differentiation 3e molecule of the T-cell antigen receptor (TCR)-cluster of differentiation 3 complex on T cells and a tumor-associated antigen on tumor cells. However, limitations of this approach include cytokine release syndrome and a limited therapeutic window. In this study, we report the generation and preclinical evaluation of SAR444200, the first NANOBODY-based TCE clinical candidate binding to TCRαβ and glypican-3 (GPC3) to coengage T cells and GPC3+ tumor cells, causing TDCC. SAR444200 bound with nanomolar to picomolar affinity to TCRαβ and GPC3, respectively, and induced in vitro TDCC against multiple human tumor cell lines with differential GPC3 expression with picomolar potency. In vivo analysis using human cancer cell line-derived xenografts (HuH-7 and HepG2) in immunodeficient mice showed complete tumor regression at doses starting from 0.7 mg/kg. In exploratory non-human primate studies, intravenous administration of SAR444200 was well tolerated up to 8 mg/kg and exhibited greater than dose-proportional clearances and dose-proportional maximum concentrations across the tested dose range. The highly potent and efficacious activity of SAR444200 in diverse models of GPC3+ tumors and the extremely wide tolerated dose range merit further development of this compound. Furthermore, NANOBODY-based TCEs developed using an anti-TCRαβ moiety may have specific advantages for the development of TCEs.

Glioblastoma (GBM) is a highly aggressive tumor primarily treated through surgery, radiotherapy, and chemotherapy. GBM radioresistance involves the activation of the Rho GTPase pathway, actin cytoskeleton polymerization, and the cytoplasmic retention of wild-type (WT) p53. Activation of DNA damage response pathways and double-strand break repair depends on the cytoplasmic availability of G-actin and its nuclear translocation, which facilitates p53 nuclear transport. In this study, we investigated whether DNA damage repair pathways induced by cisplatin (CP) and temozolomide (TMZ) are dependent on Rho pathway activity and actin cytoskeleton dynamics by generating chemoresistant GBM sublines. GBM cells expressing WT p53 displayed activation of the Rho pathway and actin polymerization when treated with TMZ or CP but showed reduced activation of DNA repair signaling, as well as lower levels of p-p53 (Ser15) and p21Cip1. TMZ-resistant clones exhibited constitutive Rho pathway activity, elevated p53 levels, and activation of DNA damage response and double-strand break repair pathways but displayed reduced levels of mismatch repair proteins. Notably, inhibition of Rho GTPases restored the sensitivity of TMZ- and CP-resistant clones, reversing either transient or permanent chemoresistance in a process entirely dependent on WT p53. GBM cells harboring mutant p53 treated with PRIMA-1 also regained sensitivity to chemotherapy following Rho pathway inhibition. These findings were corroborated in GBM spheroid tumor models treated with TMZ and CP under actin cytoskeleton polymerization inhibition. In summary, modulating Rho pathway activity and actin cytoskeleton dynamics is crucial for both the development and reversal of chemoresistance in GBM.

Antibodies against galactose-α-1,3-galactose (αGal) are among the most abundant natural antibodies in humans and have been exploited in cancer immunotherapy, with their efficacy partly attributed to complement activation. We aim to enhance this response by employing properdin [also known as factor P (FP)], the only known positive complement regulator. We expressed a membrane-anchored properdin (mFP) on mouse and human pancreatic cancer cells and assessed its ability to enhance αGal-mediated complement activation. We showed here that ectopic expression of mFP on Panc02 cells increased the deposition level of C3 in vitro and induced more potent complement-dependent cytotoxicity in the presence of human complement source. In an immunized Ggta1 knockout mouse model, which has circulating anti-αGal antibodies as a mimicry of the human system, mFP expression conferred significantly delayed tumor growth and was associated with pronounced remodeling of the immune landscape in the tumor microenvironment (TME). Specifically, we observed a marked increase in conventional type 1 dendritic cells, a reduction in tumor-associated monocytes/macrophages with a shift toward a pro-inflammatory phenotype, and a transition of CD8+ T cells toward a progenitor-exhausted state. Reconfiguring the structure of mFP to create an artificial C3 convertase binding site and incorporating an intracellular oligomerization domain improved target cell killing and monocyte-mediated phagocytosis in a human whole-blood loop model. These findings suggest that amplifying complement activation can delay tumor growth and alter the TME in the context of a murine pancreatic cancer model. Furthermore, we have developed a novel membrane-bound oligomerized FP functional unit, which effectively elicits robust complement activation.

Bitter taste receptors (T2Rs), a family of G-protein-coupled receptors, are emerging as potential therapeutic targets in head and neck squamous cell carcinoma (HNSCC). Phendione, a known T2R5 agonist, has not been previously investigated in HNSCC. In this study, we show that phendione activates endogenously expressed T2R5 in HNSCC cells and ex vivo tumor samples, inducing sustained calcium responses, reducing cell viability, and promoting apoptosis through a T2R5-dependent mechanism. Analysis of The Cancer Genome Atlas data revealed that high T2R5 expression in HNSCC tumors correlates with improved long-term disease-specific survival, suggesting a potential tumor-suppressive role for T2R5. These findings highlight T2R5 as a promising therapeutic target in HNSCC and support further investigation of phendione or other T2R5 agonists as potential anticancer agents.