Molecular Cancer Therapeutics最新文献

Antibody-drug conjugates (ADC) have recently emerged as an effective treatment option for cancer. Although the fundamental mechanisms of direct tumor cell killing by various ADC payloads have been established, their impact on the tumor microenvironment (TME) remains underexplored. To investigate this fundamental question, we generated an immunocompetent murine tumor model that maintains the expression of a clinically validated tumor-associated antigen, human HER2. We evaluated two ADCs with a shared antibody framework: trastuzumab linked to the microtubule inhibitor monomethyl auristatin E (T-MMAE) and the topoisomerase inhibitor deruxtecan (T-DXd). Treatment with T-MMAE led to a significant increase in immune cell infiltration, whereas T-DXd-treated tumors had fewer immune cells albeit comparable tumor cytotoxicity. When combined with anti-PD-1 immunotherapy, similar additive effects on the primary antitumor response were observed for both ADCs. A key qualitative difference between the two ADCs was observed in the phenotypes of myeloid APCs; T-MMAE treatment resulted in greater immune cell infiltration within the tumor, including macrophages that showed increased gene expression of F4/80, CD206, and IL10RA. In contrast, tumors treated with T-DXd exhibited a lower proportion of macrophages, but APCs in these tumors displayed heightened levels of the CD80 costimulatory molecule. The secondary antitumor response mediated by memory CD8+ T cells was crucial for the formation of immunologic memory induced by both ADCs. Therefore, our findings reveal that, after ADC-mediated tumor cytotoxicity, different ADC payloads elicit distinct immunologic responses characterized by varying levels of myeloid cell activation within the TME.

The essential role of mTOR in promoting tumorigenesis of many cancers makes it an attractive therapeutic target. However, catalytic mTOR inhibitors, which block both mTORC1 and mTORC2, result in activation of negative feedback loops as a resistance mechanism. Selective mTORC2 inhibitors are expected to have the desired anti-tumor effects without engaging resistance mechanisms; however, to date, no such mTORC2 inhibitors have been developed. Using in-silico screening and medicinal chemistry optimization, we identified several small molecules that bind to the unique mTORC2 component, SIN1. We demonstrate that this SIN1 inhibitor alters post-translational modification, protein-protein interactions, and blocks mTORC2- and rapamycin sensitive (RS) mTORC1-mediated signaling. The SIN1 inhibitor also inhibits wildtype RAS activation and downstream MAPK signaling, as well as cell proliferation of multiple cancer cell line types. SIN1 inhibition can enhance the efficacy of FDA- approved anti-neoplastic agents in vitro and may provide a novel approach for the treatment of different types of malignancies.

Intratumoral T regulatory cells (Tregs) promote an immunosuppressive tumor microenvironment and are frequently associated with a lack of response to immunotherapy. Selective targeting of intratumoral Tregs while sparing broader Tregs and effector T cell populations is an attractive strategy to enhance antitumor immune responses. CCR8 is a G protein-coupled receptor (GPCR) that is predominantly upregulated on tumor resident Tregs in a range of human solid tumors making it a promising target for their selective depletion. In preclinical studies using the mouse tumor models, anti-mouse CCR8 antibody treatment resulted in depletion of CCR8+ intratumoral Tregs, significant antitumor activity and enhanced survival in combination with anti-PD-1. CHS-114 is a highly selective, afucosylated human anti-CCR8 monoclonal antibody that is being developed as a cancer immunotherapy. CHS-114 selectively binds human CCR8 and potently kills CCR8 expressing cells by inducing antibody dependent cellular cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP). Ex vivo studies evaluating human dissociated tumor cells (DTCs) demonstrated the selectivity of CHS-114 in depleting intratumoral Tregs while sparing CCR8 negative Tregs and effector T cells. Treatment of tumor bearing human CCR8 knock-in (huCCR8KI) mice with CHS-114 resulted in significant tumor growth inhibition (62.6%) accompanied by remodeling of the tumor immune microenvironment and enhanced differentiation of a subset of cytotoxic CD8+ T cells. Based on the promising preclinical data, we are evaluating CHS-114 in clinical trials as an investigational agent for the treatment of solid tumors with and without the anti-PD-1 antibody toripalimab (NCT05635643, NCT06657144).

Statins have been reported to exert anticancer activity, varying with cancer type and specific statins. These findings suggest that more mechanistic insights into the anticancer effects of statins are needed. In this study, we interrogated the ability of statins to induce cell death and ferroptosis in melanoma and colorectal cancer. First, we showed that statins induce cell death in patient-derived melanoma cell lines and that lower expression of mevalonate pathway genes correlates with increased CD8+ T-cell infiltration and improved overall survival in patients with melanoma. We found that lipophilic statins induce cell death with features of ferroptosis. Transcriptional data also revealed system-level changes to a variety of ferroptosis-related pathways. We found that mevalonate rescued statin-induced cell death. Mechanistically, mevalonate-derived isopentyl pyrophosphate is necessary for isopentylation of tRNA [Ser]Sec, which is required for efficient synthesis of the selenoprotein ferroptosis suppressor GPX4. Given the emerging role for ferroptosis in antitumor immunity, we tested lipophilic statins, including simvastatin, alone and in combination with α-PD1 in vivo and found that simvastatin and α-PD1 promoted tumor clearance and extended survival in 20% to 60% of mice alone but in nearly 100% of mice when administered together. Simvastatin also depleted GPX4 in vivo. These results highlight the therapeutic potential of statin use in combination with immunotherapies.

Epigenetic aberrations are key drivers of multiple myeloma, yet targeted therapies exploiting epigenetic alterations have not been established. By integrating clinical and molecular datasets of patients with multiple myeloma with an unbiased genetic in vivo screen, we identified KAT8 regulatory NSL complex subunit 2 (KANSL2) as a histone posttranslational modification-associated candidate oncogene. High expression of KANSL2 was associated with adverse prognosis in patients with multiple myeloma. Genetic gain- and loss-of-function models identified a protective role of KANSL2 toward genotoxic stress. By transcriptomics, proteomics, and quantitative acetylome profiling, we identified a KANSL2-dependent specific molecular program targetable by acetylation-related modifiers. High KANSL2 levels increased sensitivity to the histone deacetylase (HDAC) inhibitor panobinostat and bromodomain and extra-terminal motif (BET) inhibitor OTX-015 and their combination. Ex vivo drug response profiling in samples from patients with relapsed/refractory multiple myeloma confirmed that high KANSL2 expression is associated with selective multiple myeloma cell killing by HDAC and BET inhibitors. Collectively, these findings position KANSL2 as a mediator of chemotherapy resistance and actionable biomarker for response to drugs targeting its epigenetic program.

CAR T-cell therapy has shown efficacy in hematological malignancies but faces challenges in solid tumors and virus-associated malignancies such as post-transplant lymphoproliferative disorder (PTLD). Various strategies, including optimization of receptor design, genetic modifications addressing immunomodulatory mechanisms and refining the manufacturing process have been explored to overcome limited in vivo persistence and tumor infiltration, antigen escape and the immunosuppressive tumor microenvironment (TME). This study investigated the effect of vitamin C (vitC) conditioning on CD19-targeting CAR T cells (vitC-CAR19-Ts) to improve efficacy of CAR T-cell therapy. VitC has been shown to influence immune responses through epigenetic regulation and oxidative stress reduction. Enhanced transduction efficiency and proliferative capacity by vitC conditioning resulted in a higher yield of CD4+ and CD8+ CAR19-Ts. VitC-CAR19-Ts exhibited faster and improved cytotoxic response towards CD19+ Nalm-6 cells and Epstein-Barr virus (EBV)-infected B-lymphoblastoid cell lines (B-LCLs), the in vitro model of PTLD. Increased demethylation was observed in TBX21 regions, which was in line with a type 1-like phenotype and higher expression of effector molecules such as Granulysin in both CD4+ and CD8+ in vitC-CAR19-Ts, providing insights into the effects of vitC conditioning. Importantly, vitC-CAR19-Ts outperformed CAR19-Ts in long-term antigen stress assays and 3D multicellular spheroid models, indicating a potentially improved in vivo functionality and tumor infiltration capacity. In summary, vitC conditioning represents a promising strategy to enhance CAR T-cell yield, cytotoxic potential and durability, complementing existing approaches to overcome the limitations of CAR T cells in the treatment of hematological malignancies and solid tumors.

The phase III study of romidepsin plus CHOP for peripheral T-cell lymphoma (PTCL) yielded negative results in the overall analysis and showed that outcomes were only improved in the T follicular helper (TFH) subgroup of PTCL, with no benefit in non-TFH PTCL. Belinostat, another histone deacetylase (HDAC) inhibitor, is now the primary candidate to test whether HDAC inhibition can improve treatment outcomes in first-line PTCL. Whether belinostat shares romidepsin's TFH-specific clinical activity remains uncertain, and therefore whether it is better to include or exclude non-TFH subtypes may be a crucial choice for a forthcoming confirmatory trial of belinostat-CHOP in first-line PTCL. We evaluated whether these agents are cross-resistant in non-TFH lymphomas by conducting in vitro drug sensitivity profiling with belinostat, romidepsin, and other pairs of mechanistically related agents in 30 non-TFH human T- and NK-cell lymphoma cultures. Sensitivities to romidepsin and belinostat were strongly correlated (ρ = 0.77, P < 10-6) and comparable with correlations observed for other same-mechanism drug pairs (e.g., doxorubicin/etoposide) and significantly higher than for drug pairs without mechanistic similarity. These findings indicate substantial cross-resistance between romidepsin and belinostat in non-TFH PTCL. If belinostat shares romidepsin's subtype-specific activity, a first-line trial of belinostat plus CHOP with broad patient enrollment may risk diluting benefit in TFH lymphomas by including non-TFH cases, whereas a TFH-focused design could maximize the likelihood of the trial's success.

Solute carrier family 16 member 2 (SLC16A2), also known as monocarboxylate transporter 8 (MCT8), is a member of the SLC16 family that exerts essential functions in the transport of elemental cell nutrients. This study explores the function of SLC16A2 in hepatocellular carcinoma (HCC) progression, particularly its impact on T-cell function. We established Slc16a2 gene knockout (Slc16a2ko) C57BL/6 mice and injected H22 cells subcutaneously to analyze tumor growth and T-cell activity in vivo. Additionally, Slc16a2fl/fl mice were crossed with Cd8aCre mice to obtain Slc16a2-Cd8a-ko mice, in which Slc16a2 was specifically knocked out in CD8+ T cells. In addition to subcutaneous models, luciferase-labeled H22 cells were injected into the liver lobe of mice for orthotopic models. SLC16A2 alteration did not affect the proliferation or migration of mouse Hepa1-6 and H22 cells in vitro though the tumorigenic activity of H22 cells was substantially reduced in Slc16a2ko and Slc16a2-Cd8a-ko C57BL/6 mice. Slc6a2 was highly expressed in exhausted T (Tex) cells, and its expression in Tex cells, as well as the population of Tex cells in tumors, was increased by lactate or other chronic stimuli. An MCT8 monoclonal antibody (mAb) reduced lactate uptake by Tex cells, thus enhancing CD8+ T-cell activity and reducing tumor growth in mice. The MCT8 mAb treatment also enhanced the efficacy of anti-PD-L1 in mice bearing tumors. This study supports that SLC16A2 contributes to Tex cell accumulation in association with increased lactate uptake and hampers immune activity in HCC, supporting SLC16A2 as a promising target to enhance immune activity in HCC management.

We previously used a myoblast model of fusion-positive rhabdomyosarcoma (FP-RMS) to show that FGF8, a PAX3-FOXO1 (P3F) transcriptional target, is required for P3F-driven tumorigenicity and, when aberrantly expressed, can maintain tumorigenicity in P3F-independent recurrent tumors. We report in this study that FGF8, FGFR1, and FGFR4 are often highly expressed in FP-RMS tumors. High FGF8 expression in FP-RMS cells is associated with high sensitivity to an FGFR4 inhibitor and a pan-FGFR inhibitor. Although downregulating FGF8 resulted in loss of sensitivity to these inhibitors, FGF8 upregulation in myoblasts decreased FGFR4 expression and sensitized the cells to an FGFR1 inhibitor and a pan-FGFR inhibitor. FGF8 downregulation of FGFR4 expression was reverted by inhibitors of FGFR1, MEK, or ERK, thus defining a signaling pathway by which FGF8 mediates this regulatory effect. Finally, high FGF8 expression in P3F-independent recurrent tumors was attributable to a rearrangement of viral long terminal repeat (LTR) sequences into the FGF8 3' untranslated region, resulting in increased FGF8 mRNA stability. These findings indicate that FGF8 exerts oncogenic effects in FP-RMS via FGFR4 and may exert oncogenic effects in P3F-independent relapses via FGFR1. Our study reveals the functional significance of FGF8 in FP-RMS and provides a rationale for preclinical studies of FGFR inhibitors in FP-RMS.

Endocrine therapy has proven to be beneficial for patients with estrogen receptor (ER) positive, HER2 negative (ER+/HER2-) breast cancer; however, de novo or acquired resistance remains a major clinical challenge. Upon progression, many of the cancers continue to be ER dependent, highlighting the opportunities for novel ER targeting therapies. Fulvestrant, a selective estrogen receptor degrader (SERD) that antagonizes and degrades ER simultaneously, has demonstrated activity in ER+/HER2- breast cancers the ability to overcome endocrine resistance. Fulvestrant has limitations including challenging administration by intramuscular injection and poor bioavailability, resulting in sub-optimal drug exposure, hence several next generation oral SERDs with improved drug properties have been developed and are currently being evaluated in the clinic for their therapeutic benefit. Here, we describe the discovery of ZN-c5, an orally bioavailable SERD with favorable pharmacokinetic properties and potent activities against both wild-type and mutant ER. In vivo studies showed that ZN-c5 treatment resulted in significant tumor growth inhibition in a variety of breast cancer models and patient-derived xenograft models that harbor ESR1 mutations. Combination with CDK4/6 inhibitors or PI3K pathway inhibition enhanced anti-tumor effects compared with single agent alone. ZN-c5 also demonstrated bone protective effect as observed in a mouse osteoporosis model. These data support the clinical utility of ZN-c5 as monotherapy and as a combination therapy for patients with ER+/HER2- breast cancers. While encouraging plasma exposure and tolerability have been observed for ZN-c5 in patients, further studies are needed to optimize its therapeutic efficacy.