Molecular Cancer Therapeutics最新文献

Despite new therapies, many patients with non-Hodgkin lymphoma (NHL) relapse and need more effective salvage therapies. This study (NCT02483000) evaluated the safety of B9E9-FP, a tetrameric single-chain anti-CD20-streptavidin fusion protein used in pretargeted radioimmunotherapy, when combined with BEAM and autologous stem cell transplantation (ASCT) for patients with NHL. Patients with high-risk NHL received B9E9-FP on day -17, clearing agent on day -15, and DOTA-biotin (DOTA-Bt) equally divided and labeled with dose-escalated yttrium-90 (90Y) or with indium-111 (for imaging) on day -14. BEAM chemotherapy started at day -7 before stem cell infusion. Three patients with NHL (mantle cell lymphoma, transformed diffuse large B-cell lymphoma, and de novo diffuse large B-cell lymphoma), ages 52 to 62 years, were treated with 30, 50, or 70 mCi (1,110, 1,850, or 2,590 MBq) 90Y/m2 before ASCT without any dose-limiting toxicity. One case of diarrhea (grade 2) and one case of rash (grade 1) were possibly associated with B9E9-FP or DOTA-Bt, respectively. Pharmacokinetic studies showed peak blood biological percent injected dose per gram blood (% ID/g) of 90Y-DOTA-Bt at 15 minutes after infusion (14.8%-49.4% ID), with only 0.82% to 2.59% ID after 72 hours. Uptake was preferential at bone marrow (1.73-5.96 cGy/mCi injected) and spleen (2.4-4.17 cGy/mCi injected) compared with lungs (0.19-0.48 cGy/mCi). Unbound 90Y-DOTA-Bt was excreted renally without any renal dysfunction noted up to 2 years later. Two of the three enrolled patients are alive and in remission 3.5 to 4.9 years after transplant. Pharmacokinetic, dosimetry, and outcome data support that B9E9-FP pretargeted radioimmunotherapy combined with 90Y-augmented ASCT DOTA-Bt is feasible.

Epigenetic aberrations are key drivers of multiple myeloma (MM), yet targeted therapies exploiting epigenetic alterations have not been established. By integrating clinical and molecular MM patient data sets with an unbiased genetic in vivo screen, we identified KAT8 regulatory NSL complex subunit 2 (KANSL2) as a histone posttranslational modification (PTM)-associated candidate oncogene. High expression of KANSL2 was associated with adverse prognosis in MM patients. Genetic gain and loss of function models identified a protective role of KANSL2 towards 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 relapsed/refractory MM patient samples confirmed that high KANSL2 expression is associated with selective MM 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.

Breast cancer brain metastasis (BCBM) remains a clinical challenge marked by limited therapeutic options and poor survival rates. Approximately 30% of all metastatic breast cancer patients develop BCBM, with the highest incidence in patients with aggressive molecular subtypes, including triple-negative breast cancer (TNBC). TNBC patients with brain metastasis experience rapid disease progression and significantly reduced survival times due to a lack of targeted treatments that can penetrate the blood-brain barrier (BBB) and effectively control metastatic expansion. Current treatment options, such as whole-brain radiotherapy and chemotherapy, offer limited efficacy and are associated with significant toxicities, underscoring the urgent need for novel therapeutics that can target BCBM directly. We developed innovative colchicine binding site inhibitors (CBSIs) targeting tubulin, SB-216 and SP-1-39, that show potent preclinical efficacy against brain and extracranial metastases in BCBM models. Both CBSIs cross the BBB, inhibit cell growth and migration, and induce apoptosis with low nM potencies, similar to Azixa (MPC-6827), another CBSI previously evaluated in clinical trials. SB-216 reduced brain and concurrent extracranial metastases in a preventive dosing paradigm, extending overall survival. SB-216 also suppressed the expansion of pre-established brain lesions. In a taxane-refractory TNBC PDX model, SP-1-39 therapy markedly reduced brain and extracranial tumor burden. Together, these results highlight the promising therapeutic potential of SB-216 and SP-1-39 in treating taxane-sensitive or -resistant BCBM, filling a critical gap in TNBC management by offering targeted treatments that can cross the BBB and combat chemorefractory disease.

AXL is an important negative regulator of type I interferon (IFN) responses during viral infections. In the context of tumors, AXL is associated with driving tumor progression, spread, immune evasion, and therapy resistance. AXL regulation of tumor cell intrinsic IFN responses remains unexplored. We show that AXL suppresses tumor intrinsic IFN responses by inhibiting the cytosolic DNA sensor cGAS via an AKT-dependent pathway. AXL inhibition in combination with chemo-immunotherapy demonstrated potent anti-tumor effects in poorly immunogenic tumors that are refractory to immunotherapy. The inhibition of AXL correlated with increased cGAMP levels, activation of IFN, and enhanced infiltration of T cells and NK cells into the tumor microenvironment. These findings reveal a novel role for AXL in suppressing IFN within tumors and support AXL targeting as a promising strategy in conjunction with chemo-immunotherapy for treating therapy-resistant tumors.

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, where 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 proliferation or migration of mouse Hepa1-6 and H22 cells in vitro, though, tumorigenic activity of H22 cells was substantially reduced in Slc16a2ko and Slc16a2-Cd8a-ko C57BL/6 mice. Slc6a2 was highly expressed in Tex cells, and its expression in Tex, 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 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. While 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 LTR sequences into the FGF8 3' UTR 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.

For HER2-positive advanced gastric cancer (GC), a recent major therapeutic advancement is the development of trastuzumab deruxtecan (T-DXd), a HER2-directed antibody-drug conjugate. In this disease, simultaneously targeting HER2 and HER3 pathways has the potential to be a promising therapeutic strategy. However, the therapeutic approach of combining T-DXd with pertuzumab, which disrupts HER2-HER3 heterodimerization, has not yet been explored in GC, making this study a pioneering effort. In vitro, T-DXd efficacy correlated with high levels of membrane HER2 expression. Among the 12 cell lines tested, two cell lines (NCI-N87 and OE19) confirmed as HER2 3+ by immunohistochemistry showed the most effective proliferation inhibition by T-DXd. When comparing NCI-N87 and OE19, HER2-HER3 dimerization was found to be more abundant in NCI-N87, and combination treatment with pertuzumab and T-DXd showed synergy in cell growth inhibition in NCI-N87, but not in OE19. NRG1 stimulation attenuated the antiproliferative effect of T-DXd. This attenuation of T-DXd activity by NRG1 was partially reversed by the addition of pertuzumab in NCI-N87, but not in OE19. Notably, the combination of T-DXd and pertuzumab enhanced membrane HER2 internalization more effectively in NCI-N87 than in OE19. In vivo mouse experiments using NCI-N87 cells showed the combination treatment significantly suppressed tumor growth compared to either monotherapy. Taken together, our findings suggest that dual targeting of HER2 and HER3 with T-DXd and pertuzumab may improve therapeutic outcomes in HER2-positive GC, particularly in tumors enriched with HER2-HER3 heterodimers. These preclinical data provide strong rationale for clinical trials evaluating this combination strategy in HER2-positive GC.

Lynch syndrome (LS) is characterized by the development of microsatellite instable (MSI) cancers that share neoantigens, offering an opportunity for targeted immunotherapy. NOUS-209 is a heterologous prime-boost cancer vaccine in clinical development, employing viral vectors encoding 209 shared neoantigen peptides derived from frameshift mutations (FSMs) commonly found in MSI tumors. In this study, we investigated the presence and dynamics of NOUS-209 targeted FSMs in both primary and metachronous LS-associated cancers. Whole-exome sequencing was performed for 73 tumors, including 58 colorectal cancers (CRC) and 15 urothelial cancers (UC), from 58 individuals with confirmed LS. A median of 57 FSMs per CRC and 24 FSMs per UC was observed, with similar FSM burdens in both primary and metachronous tumors. Analysis of nine matched primary-metachronous tumor pairs revealed evidence of immune editing: FSMs predicted to encode highly immunogenic neoepitopes were selectively lost in metachronous tumors, while those with lower predicted immunogenicity were retained. Importantly, all subsequent primary cancers acquired novel FSMs encoding neoantigens with strong predicted HLA-binding affinity, supporting the rationale for NOUS-209-mediated immune interception. These findings demonstrated that NOUS-209 FSMs are present in both CRCs and UCs in LS, expanding the therapeutic potential of NOUS-209 beyond CRC. Moreover, the emergence of novel targetable FSMs in metachronous tumors suggests that NOUS-209 immunotherapy may be effective in the prevention of both primary and metachronous LS-associated cancers.

Claudin18.2 (CLDN18.2)-targeted chimeric antigen receptor T (CAR-T) cell therapy has shown promising antitumor activity in gastrointestinal cancers. However, limited persistence in solid tumors and on-target off-tumor (OTOT) toxicity remain significant challenges. Here, we report on the preclinical development of a nanobody-based CLDN18.2-targeted CAR-T (IMC002) with effectiveness and safety in CLDN18.2-positive gastric and pancreatic cancer and present an efficacious clinical case. IMC002 exhibited robust antitumor activity and tolerability in multiple CLDN18.2-positive cell-derived xenograft and patient-derived xenograft models of gastric and pancreatic cancer with reduced OTOT toxicity. In vivo pharmacological studies revealed that peak concentrations of CAR gene DNA copies in total DNA in the tumor and lung tissues occurred on seven days after administration, while the peak in stomach tissues was observed an additional seven days later. Toxicity studies showed no obvious body weight loss induced by IMC002. The highest non-severely toxic dose was 5×108 CAR-T cells/kg. In the clinical case report, we present a case with unresectable advanced gastric cancer achieved pathological complete response 10 months after IMC002 infusion and no signs of recurrence were indicated in subsequent clinical and radiological follow-ups. IMC002 shows effectiveness and safety in CLDN18.2-positive gastric and pancreatic cancer and its favorable profiles support further clinical development.

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. Here, 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 anti-cancer agents.