Induce Tumor Cell Apoptosis Research Articles

Synthesis of Fe3O4 core/MIL-100(Fe) shell nanocomposites for tumor chemo-ferroptosis combination therapy and MR imaging

The application of both chemotherapy and ferrotherapy together has shown great potential in increasing the effectiveness of cancer treatment. To achieve such a combination, we herein have synthesized Fe3O4 core/MIL-100(Fe) shell nanocomposites (FM) that can be used for tumor chemo-ferroptosis combination therapy. In these nanocomposites, the anticancer drug 10-hydroxycamptothecin (HCPT) and iron ions could be co-delivered into tumors. On one hand, the released HCPT molecules can enter the cell nucleus and bind with DNA, resulting in induction of tumor cell apoptosis. On the other hand, the iron ions could react with H2O2 leading to the production of ROS through the Fenton reaction, thereby triggering tumor cell ferroptosis. Consequently, a superior antitumor effect was achieved through the combination of the apoptosis and ferroptosis. Additionally, the Fe3O4 core endowed FM with high performance for magnetic resonance imaging, which further provided novel avenues for imaging guidance therapy. Therefore, we anticipate that application of these nanocomposites could have great potential in the field of tumor therapy.

Menthol-modified paclitaxel multifunctional cationic liposomes cross the blood-brain barrier and target glioma stem cells for treatment of glioblastoma

Glioblastoma is the most malignant glioma of the central nervous system, as the presence of cerebral glioma stem cells and the blood-brain barrier hamper its treatment. Menthol can improve blood-brain barrier permeability. Cationic liposomes can interact with negatively charged macromolecules on tumor neovascular endothelial cells to produce passive targeting. Ginsenoside Rh2 can replace cholesterol to make liposomes more stable. Paclitaxel has an excellent antitumor effect. Therefore, in this study, menthol-modified paclitaxel cationic liposomes were constructed to cross the blood-brain barrier and targeted the tumor, to achieve safe and effective treatment of glioblastoma. We discovered that the addition of DC-chol liposomes can enhance the uptake of C6 glioma stem cells, promote the apoptosis of C6 glioma stem cells and inhibit the proliferation of tumor cells in vitro. We found that targeted liposomes could cross the blood-brain barrier and target tumor sites to induce tumor cell apoptosis in vivo. In brief, menthol-modified paclitaxel cationic liposomes offer a safer approach to the treatment of glioblastoma.

Controlled domain gels with a wide stiffness gradient simultaneously promote bone regeneration and suppress tumor recurrence through DAPK activity

The reconstruction of bone defects following bone tumor resection pose significant challenges, including high risks for tumor recurrence. To address these challenges, we designed controlled-domain gels that possessed exceptional anti-tumorigenic effectiveness and osteogenic activity. This was achieved through the selection of an amino-acid-based low-molecular-weight gels (LMWGs) with superior biocompatibility and antitumor efficacy, and further construction of three-domain structure with a large-range stiffness gradient, through the assembly/disassembly of LMWGs inside a stable methacrylated alginate (AlgMA) network using photopolymerization. Such layered design not only constructed a top anti-tumorigenic domain at 0.6 kPa and a bottom osteogenic domain at 500 kPa, allowing for selectively inducing tumor cell apoptosis and promoting osteogenic differentiation of mesenchymal stem cells (MSCs), but also generated a gradient selectively confining the migration of tumor cells along soft-to-hard direction, without affecting the recruiting of MSCs toward the injury sites. In particular, the critical involvement of the DAPK-mediated signaling cascades might lead to the selected apoptosis of tumor cells on LMWG domain. The in-vivo results further suggested that multi-domain gel effectively inhibited tumor growth and displayed excellent bone-forming activity. Overall, such strategies could advance our fundamental understanding of the bone tumor postoperative treatment, in addition to offering new therapeutic opportunities.

The augmentation of cytotoxic immune cell functionality through physical exertion bolsters the potency of chemotherapy in models of mammary carcinoma.

Mammary carcinoma, a pervasive and potentially lethal affliction, is conjectured to be profoundly influenced by physical exercise, both in prophylaxis and therapeutic contexts. This study endeavors to explore the repercussions of exercise training on the progression of mammary carcinoma, particularly the mechanisms by which the amalgamation of an exercise regimen and doxorubicin induces tumor cell apoptosis. Female BALB/c mice were categorized into four distinct groups: A sedentary group (SED), an exercise group (Ex), a doxorubicin group (Dox, 5 mg/kg), and a combined treatment group (Dox + Ex). The exercise training lasted for 21 days and included aerobic rotarod exercise and resistance training. The impact of exercise training on tumor growth, immune cell proportions, inflammatory factor levels, and cell apoptosis pathway was assessed. Exercise training significantly curtailed tumor growth in a mouse model of breast cancer. Both the Ex and Dox groups exhibited significant reductions in tumor volume and weight (p < 0.01) in comparison to the SED group, while the Dox + Ex group had a significantly lower tumor volume and weight than the Dox group (p < 0.01). Exercise training also significantly increased the proportion of NK and T cells in various parts of the body and tumor tissue, while decreasing tumor blood vessels density. Exercise training also increased IL-6 and IL-15 levels in the blood and altered the expression of apoptosis-related proteins in tumor tissue, with the combined treatment group showing even more significant changes. Physical training improves the effectiveness of doxorubicin in treating breast cancer by activating cytotoxic immune cells, releasing tumor suppressor factors, and initiating mt-apoptosis, all while mitigating the adverse effects of chemotherapy.

Active targeted delivery of theranostic thermo/pH dual-responsive magnetic Janus nanoparticles functionalized with folic acid/fluorescein ligands for enhanced DOX combination therapy of rat glioblastoma.

Doxorubicin (DOX), a chemotherapy drug, has demonstrated limited efficacy against glioblastoma, an aggressive brain tumor with resistance attributed to the blood-brain barrier (BBB). This study aims to overcome this challenge by proposing the targeted delivery of magnetic Janus nanoparticles (MJNPs) functionalized with folic acid ligands, fluorescent dye, and doxorubicin (DOX/MJNPs-FLA). The properties of these nanoparticles were comprehensively evaluated using bio-physiochemical techniques such as Fourier transform infrared (FTIR) spectroscopy, dynamic light scattering (DLS), zeta potential analysis, high-resolution transmission electron microscopy (HR-TEM), vibrating sample magnetometry (VSM), fluorescence microscopy, MTT assay, hemolysis assay, and liver enzyme level evaluation. Dual-controlled DOX release was investigated under different pH and temperature conditions. Additionally, the impact of DOX/MJNPs-FLA on apoptosis induction in tumor cells, body weight, and survival time of cancerous animals was assessed. The targeted delivery system was assessed using C6 and OLN-93 cell lines as representatives of cancerous and healthy cell lines, respectively, alongside Wistar rat tumor-bearing models. Results from Prussian blue staining and confocal microscopy tests demonstrated the effective targeted internalization of MJNPs-FLA by glioblastoma cells. Additionally, we investigated the biodistribution of the nanoparticles utilizing fluorescence imaging techniques. This enabled us to track the distribution pattern of MJNPs-FLA in vivo, shedding light on their movement and accumulation within the biological system. Furthermore, the combination of chemotherapy and magnetic hyperthermia exhibited enhanced efficacy in inducing apoptosis, as evidenced by the increase of the pro-apoptotic Bax gene and a decrease in the anti-apoptotic Bcl-2 gene. Remarkably, this combination treatment did not cause any hepatotoxicity. This study highlights the potential of DOX/MJNPs-FLA as carriers for therapeutic and diagnostic agents in the context of theranostic applications for the treatment of brain malignancies. Additionally, it demonstrates the promising performance of DOX/MJNPs-FLA in combination treatment through passive and active targeting.

Copper selective 8-aminoquinoline based tetradentate chelators as anticancer agents.

Cancer cell proliferation and metastasis are known to be dependent on angiogenesis which is regulated by several parameters including copper availability. Tetradentate monoquinoline (TDMQ) ligands constitute a series of chelators tailored to regulate copper homeostasis due to their specificity for copper(ii) with respect to Cu(i) or other biometals like iron or zinc. One of these chelators, TDMQ20 efficiently inhibits both proliferation and migration of several human cancer cell lines, better than the reference drug 5-fluorouracil, and with higher selectivity indexes with respect to non-cancer human cells. The biological activity of TDMQ20 may be driven by the coordination chemistry of copper, and the ability of this chelator to restore copper homeostasis and its subsequent redox properties. The anticancer mechanism of action of TDMQ20 involves intracellular production of reactive oxygen species, drastic mitochondrial damages and induction of tumor cell apoptosis. These data support the selection of TDMQ20 as drug-candidate against several human cancers.

Traditional Chinese Medicine for Cancer Treatment.

In recent years, due to advancements in medical conditions and the development of scientific research, the fundamental research of TCM antitumor treatments has progressed from the cellular level to the molecular and genetic levels. Previous studies have demonstrated the significant role of traditional Chinese medicine (TCM) in antitumor therapy through various mechanisms and pathways. Its mechanism of action is closely associated with cancer biology across different stages. This includes inhibiting tumor cell proliferation, blocking invasion and metastasis to surrounding tissues, inducing tumor cell apoptosis, inhibiting tumor angiogenesis, regulating immune function, maintaining genome stability, preventing mutation, and regulating cell energy metabolism. The use of TCM for eliciting antitumor effects not only has a good therapeutic effect and low side effects, it also provides a solid theoretical basis for clinical treatment and medication. This paper reviews the mechanism of the antitumor effects of TCM based on tumor characteristics. Through our review, we found that TCM not only directly inhibits tumors, but also enhances the body's immunity, thereby indirectly inducing an antitumor effect. This function aligns with the TCM theory of "strengthening the body's resistance to eliminate pathogenic factors". Furthermore, TCM will play a significant role in tumor treatment in clinical settings.

A copper-platinum nanoplatform for synergistic photothermal and chemodynamic tumor therapy via ROS outburst and GSH exhaustion.

A multifunctional nanoplatform is obtained by modifying copper hexacyanoferrate (Cu-HCF) nanozyme with hyaluronic acid (HA) and further loading platinum (Pt) nanoparticles. This Cu-HCF-HA@Pt platform shows peroxidase-like and glutathione oxidase-like dual-enzyme catalytic activities and photothermal properties, enabling synergistic chemodynamic and photothermal tumor therapy. HA binds to the CD44 receptor, which is highly expressed on the exterior surface of tumor cells, endowing the nanoplatform with tumor specificity. Cu-HCF-HA@Pt catalyzes the decomposition of H2O2 to produce abundant hydroxyl radicals within tumor cells, increasing intracellular oxidative stress levels and inducing tumor cell apoptosis. Meanwhile, Cu-HCF-HA@Pt catalyzes the conversion of intracellular reduced glutathione (GSH) to oxidized glutathione, resulting in GSH exhaustion. The conversion of CuII to CuI in Cu-HCF via a Fenton-like reaction can improve the peroxidase-like property of Cu-HCF-HA@Pt. After the probe is targeted to the tumor site, irradiation by an 808 nm near-infrared laser causes local heating and brings about photothermal tumor apoptosis when reaching 45 °C. The prepared Cu-HCF-HA@Pt combines nanozyme-catalyzed therapy with photothermal therapy to induce apoptosis in tumor cells.

Aspirin Inhibits Colorectal Cancer via the TIGIT-BCL2-BAX pathway in T Cells.

The T cell immunoglobulin and ITAM domain (TIGIT) is a recently discovered synergistic co-suppressor molecule that plays an important role in immune response and tumor immune escape in the context of cancer. Importantly, CD155 acts as a receptor for TIGIT, and CD155 signaling to immune cells is mediated through interactions with the co-stimulatory immune receptor CD226 (DNAM-1) and the inhibitory checkpoint receptors TIGIT and CD96. Aspirin (ASA) has been shown to reduce the growth and survival of colorectal cancer (CRC) cells, but the immunological mechanisms involved have not been sufficiently elucidated. In the present study the effects of aspirin on CRC in mice and on Jurkat cells were investigated. Aspirin may suppress the expression of TIGIT on T cells and Regulatory T cells (Tregs) and inhibit T cell viability, and therefore induce tumor cell apoptosis. TIGIT is expressed at higher levels on infiltrating lymphocytes within CRC tumor tissue than adjacent. Further, aspirin could inhibit Jurkat cell proliferation and induce apoptosis via downregulation of TIGIT expression and the anti-apoptosis B cell lymphoma 2 (BCL2) protein and upregulation of BCL2-associated X protein (BAX) expression. The present study suggests that aspirin can inhibit specific aspects of T cell function by reducing interleukin-10 and transforming growth factor-β1 secretion via the TIGIT-BCL2-BAX signaling pathway, resulting in improved effector T cell function that inhibits tumor progression.

Genetically engineered cellular nanoparticles loaded with curcuminoids for cancer immunotherapy.

Background: Inducing immunogenic cell death (ICD) is a promising strategy to enhance immune responses for immune checkpoint blockade (ICB) therapy, but the lack of a simple and effective platform to integrate ICD and ICB therapy limits their clinical application. Methods: Here, we developed programmed cell death protein 1 (PD1)-overexpressing genetically engineered nanovesicles (NVs)-coated curcumin (Cur)-loaded poly (lactic-co-poly-polyglycolic acid) nanoparticles (PD1@Cur-PLGA) to integrate ICD and ICB therapy for enhancing tumor immunotherapy. Results: Genetically engineered NVs greatly enhanced the tumor targeting of nanoparticles, and the PD1 on NVs dramatically blocked the PD1/PDL1 signaling pathway and stimulated antitumor immune responses. Meanwhile, the delivered Cur successfully induced tumor cell apoptosis and activated ICD by inhibiting NF-κB phosphorylation and Bcl-2 protein expression and activating caspase and Bax apoptotic signaling. By synergizing the ICD effect of Cur and the PD1/PDL1 axis blocking function of genetically engineered NVs, the PD1@Cur-PLGA enhanced the intratumoral infiltration rate of mature dendritic cells and CD8+ T cells in tumor tissues, resulting in significantly inhibiting tumor growth in breast and prostate tumor-bearing mouse models. Conclusion: This synergistic ICD and ICB therapy based on genetically engineered NVs provides a low-cost, safe, and effective strategy to enhance cancer immunotherapy.

Unveiling the therapeutic potential of airpotato yam rhizome against colorectal cancer: a network pharmacology approach.

The objective of this investigation was to elucidate the key active compounds and molecular mechanisms underlying the therapeutic potential of airpotato yam rhizome (AYR) in colorectal cancer (CRC) treatment. By utilizing network pharmacology and molecular docking, key targets and signaling pathways of AYR against CRC were predicted and subsequently validated in cellular and mouse xenograft models. This study initially predicted that quercetin was the primary compound in AYR that might have potential efficacy against CRC and that EGFR and AKT1 could be the main targets of AYR, with the EGF/EGFR-induced PI3K/AKT signaling pathway potentially playing a crucial role in the anti-CRC effects of AYR. Molecular docking analysis further indicated a strong binding affinity between quercetin and EGFR, primarily through hydrogen bonds. Additionally, the AYR-derived drug-containing serum was found to inhibit the PI3K/AKT signaling pathway, as demonstrated by decreased levels of p-PI3K, p-AKT, and BCL2, which ultimately led to enhanced apoptosis of HCT116 and HT29 cells. The potential antitumor effects of AYR were investigated in nude mouse xenograft models of human HCT116 and HT29 cells, in which AYR was found to induce tumor cell apoptosis and inhibit tumor formation. AYR may promote CRC cell apoptosis by suppressing the PI3K/AKT signaling pathway, which provides a basis for further research on the safe and effective use of AYR for the treatment of CRC.

Sinularin stabilizes FOXO3 protein to trigger prostate cancer cell intrinsic apoptosis

Sinularin, a natural product that purified from soft coral, exhibits anti-tumor effects against various human cancers. However, the mechanisms are not well understood. In this study, we demonstrated that Sinularin inhibited the viability of human prostate cancer cells in a dose-dependent manner and displayed significant cytotoxicity only at high concentration against normal prostate epithelial cell RWPE-1. Flow cytometry assay demonstrated that Sinularin induced tumor cell apoptosis. Further investigations revealed that Sinularin exerted anti-tumor activity through intrinsic apoptotic pathway along with up-regulation of pro-apoptotic protein Bax and PUMA, inhibition of anti-apoptotic protein Bcl-2, mitochondrial membrane potential collapses, and release of mitochondrial proteins. Furthermore, we illustrated that Sinularin induced cell apoptosis via up-regulating PUMA through inhibition of FOXO3 degradation by the ubiquitin–proteasome pathway. To explore how Sinularin suppress FOXO3 ubiquitin–proteasome degradation, we tested two important protein kinases AKT and ERK that regulate FOXO3 stabilization. The results revealed that Sinularin stabilized and up-regulated FOXO3 via inhibition of AKT- and ERK1/2-mediated FOXO3 phosphorylation and subsequent ubiquitin–proteasome degradation. Our findings illustrated the potential mechanisms by which Sinularin induced cell apoptosis and Sinularin may be applied as a therapeutic agent for human prostate cancer.

NIR light-controlled DNA nanodevice for amplified mRNA imaging and precise gene therapy

Accurately delivering antisense oligonucleotides (ASOs) to tumor cells for gene therapy poses a significant challenge. To address this issue, we develop a NIR light-activable DNA nanodevice to target survivin mRNA and simultaneously release ASOs in tumor cells, which allows high-precision spatiotemporal imaging and efficient gene therapy. The concept is based on upconversion nanoparticles, which can convert NIR light into UV emissions to activate an entropy-driven DNA walking system for mRNA recognition in tumor cells. The intramolecular toehold-mediated entropy-driven catalytic reaction generates a large amount of Bcl-2 ASOs, which allows accurate delivery of ASOs for gene therapy due to the specific targeting of mRNA in tumor cells. The results from in vitro and in vivo experiments show that the NIR light-activated DNA nanodevice can detect mRNA with high sensitivity by DNA walking amplification and high precision in gene delivery. Moreover, the released ASOs from DNA walking system down-regulate the expression of Bcl-2 anti-apoptosis protein and induce tumor cell apoptosis, thereby suppressing tumor growth without a transfection reagent. The NIR-light-controlled DNA nanodevice holds great potential for precise gene therapy in clinical applications.

Strengthening the Combinational Immunotherapy from Modulating the Tumor Inflammatory Environment via Hypoxia-Responsive Nanogels.

Despite the success of immuno-oncology in clinical settings, the therapeutic efficacy is lower than the expectation due to the immunosuppressive inflammatory tumor microenvironment (TME) and the lack of functional lymphocytes caused by exhaustion. To enhance the efficacy of immuno-oncotherapy, a synergistic strategy should be used that can effectively improve the inflammatory TME and increase the tumor infiltration of cytotoxic T lymphocytes (CTLs). Herein, a TME hypoxia-responsive nanogel (NG) is developed to enhance the delivery and penetration of diacerein and (-)-epigallocatechin gallate (EGCG) in tumors. After systemic administration, diacerein effectively improves the tumor immunosuppressive condition through a reduction of MDSCs and Tregs in TME, and induces tumor cell apoptosis via the inhibition of IL-6/STAT3 signal pathway, realizing a strong antitumor effect. Additionally, EGCG can effectively inhibit the expression of PD-L1, restoring the tumor-killing function of CTLs. The infiltration of CTLs increases at the tumor site with activation of systemic immunity after the combination of TIM3 blockade therapy, ultimately resulting in a strong antitumor immune response. This study provides valuable insights for future research on eliciting effective antitumor immunity by suppressing adverse tumor inflammation. The feasible strategy proposed in this work may solve the urgent clinical concerns of the dissatisfactory checkpoint-based immuno-oncotherapy.

The mechanism and application of traditional Chinese medicine extracts in the treatment of lung cancer and other lung-related diseases.

Lung cancer stands as one of the most prevalent malignancies worldwide, bearing the highest morbidity and mortality rates among all malignant tumors. The treatment of lung cancer primarily encompasses surgical procedures, radiotherapy, and chemotherapy, which are fraught with significant side effects, unfavorable prognoses, and a heightened risk of metastasis and relapse. Although targeted therapy and immunotherapy have gradually gained prominence in lung cancer treatment, diversifying the array of available methods, the overall recovery and survival rates for lung cancer patients remain suboptimal. Presently, with a holistic approach and a focus on syndrome differentiation and treatment, Traditional Chinese Medicine (TCM) has emerged as a pivotal player in the prognosis of cancer patients. TCM possesses characteristics such as targeting multiple aspects, addressing a wide range of concerns, and minimizing toxic side effects. Research demonstrates that Traditional Chinese Medicine can significantly contribute to the treatment or serve as an adjunct to chemotherapy for lung cancer and other lung-related diseases. This is achieved through mechanisms like inhibiting tumor cell proliferation, inducing tumor cell apoptosis, suppressing tumor angiogenesis, influencing the cellular microenvironment, regulating immune system function, impacting signal transduction pathways, and reversing multidrug resistance in tumor cells. In this article, we offer an overview of the advancements in research concerning Traditional Chinese Medicine extracts for the treatment or adjunctive chemotherapy of lung cancer and other lung-related conditions. Furthermore, we delve into the challenges that Traditional Chinese Medicine extracts face in lung cancer treatment, laying the foundation for the development of diagnostic, prognostic, and therapeutic targets.

The role of kaempferol in gynaecological malignancies: progress and perspectives.

Kaempferol, a flavonoid derived from various herbs such as cocoyam, propolis, and grapefruit, has garnered interest due to its numerous pharmacological benefits, including anti-inflammatory, antioxidant, and anti-diabetic properties. Kaempferol has been shown to possess notable anti-tumour bioactivity, indicating potential for treating gynaecological malignancies. To date, numerous studies have demonstrated the potential of kaempferol to induce tumour cell apoptosis, inhibit proliferation, and prevent metastasis and invasion in several gynaecological malignancies, including breast, ovarian and endometrial cancers. However, there is currently insufficient research investigating the efficacy of kaempferol for the treatment of gynaecological malignancies, and a lack of systematic review of its mechanism of action. Therefore, this review is founded on a literature analysis of the anticancer effects of kaempferol on gynaecological malignancies. The goal is to provide valuable reference material for scientific researchers and medical practitioners.

Targeted Therapy of Central Nervous System Acute Lymphoblastic Leukemia with an Integrin α6-Targeted Self-Assembling Proapoptotic Nanopeptide

There is currently no effective targeted therapeutic strategy for the treatment of central nervous system acute lymphoblastic leukemia (CNS-ALL). Integrin α6 is considered a potential target for CNS-ALL diagnosis and therapy because of its role in promoting CNS-ALL disease progression. The targeted peptide D(RWYD) (abbreviated RD), with nanomolar affinity to integrin α6 was identified by peptide scanning techniques such as alanine scanning, truncation, and D-substitution. Herein, we developed a therapeutic nanoparticle based on the integrin α6-targeted peptide for treating CNS-ALL. The self-assembled proapoptotic nanopeptide D(RWYD)-D(KLAKLAK)2-GD(FFY) (abbreviated RD-KLA-Gffy) contains the integrin α6-targeted peptide RD, the well-known proapoptotic peptide D(KLAKLAK)2 (abbreviated KLA), and the self-assembling tetrapeptide GD(FFY) (abbreviated Gffy). The functional mechanism of RD-KLA-Gffy is clarified using different experiments. Our results demonstrate that RD-KLA-Gffy is highly enriched in CNS-ALL lesions and induces tumor cell apoptosis, thus reducing CNS-ALL disease burden and prolonging the survival of CNS-ALL mice without obvious toxicity. Moreover, the combined use of RD-KLA-Gffy and methotrexate (MTX) shows a potent antitumor effect in treating CNS-ALL, indicating that RD-KLA-Gffy plays an important role in suppressing CNS-ALL progression either as a single agent or in combination with MTX, which shows promise for application in CNS-ALL therapy.

Abstract A137: Pharmacokinetics and pharmacodynamics of IGM-8444, a first-in-class engineered pentameric DR5-targeting agonist IgM monoclonal antibody, in patients with R/R and newly diagnosed cancers

Abstract Introduction: IGM-8444 is an engineered DR5 agonist IgM antibody with 10 binding sites that efficiently multimerizes DR5 to induce tumor cell apoptosis. The first-in-human Phase 1a/1b study of IGM-8444 (NCT04553692) is ongoing, and preliminary results show that IGM-8444 is well-tolerated as a single agent (SA) and in combination with chemotherapeutic and targeted agents. Encouraging efficacy is also observed with IGM-8444 combined with FOLFIRI +/- bevacizumab (bev) in patients with relapsed/refractory mCRC. Here we present pharmacokinetic (PK) and pharmacodynamic biomarker data from Phase 1a participants treated with IGM-8444 as SA or in combination at doses of 0.15 to 5 mg/kg given weekly (QW) or 0.3 to 10 mg/kg given every 2 weeks (Q2W). Methods: Blood samples for PK and biomarker analysis were collected at multiple timepoints during cycles 1 and 2. Sparse sampling was utilized at later cycles. Plasma biomarker evaluation included measurement of M30 by ELISA and total caspase-3 (casp-3) by MSD. Tumor biomarkers were assessed in baseline and on-treatment tissue through immunohistochemistry for DR5 and cleaved caspase-3 (CC3). Initial population PK modeling was conducted to assess the PK characteristics of IGM-8444 as SA and in combination, and to enable simulations of different doses and dosing regimen scenarios. Results: Treatment-related increases in plasma levels of apoptotic markers casp-3 (up to 25-fold) and M30 (up to 6-fold) were observed across dose levels. These changes occurred independently of any ALT or AST fluctuations, suggesting tumor-specific apoptosis induction. Dose-dependent increases in casp-3 and CC3 were observed in blood and tumor, respectively, indicating activation of DR5 pathway. At 3 mg/kg, on-treatment tumor CC3 levels were up to 10-fold higher in FOLFIRI combo, signifying enhanced apoptosis when IGM-8444 is combined with chemotherapy. Population PK analysis indicates that IGM-8444 PK is best described by a two-compartment model with parallel linear and nonlinear clearance. Terminal half-life at 10 mg/kg Q2W was &amp;gt;2 days. PK simulations suggest that IGM-8444 administered at 3 or 10 mg/kg Q2W sustains average concentrations within the range as those observed at efficacious doses of IGM-8444 in preclinical mouse tumor models, where SA IGM-8444 exhibits dose-dependent efficacy with no evidence of a bell-shaped response. To date, ADAs have been detected in ~25% of participants. ADA titers in confirmed ADA-positive participants remain relatively low and the available data do not indicate a significant effect of ADAs on the PK of IGM-8444. Conclusions: Pharmacodynamic changes in blood and tissue confirm the biologic activity of IGM-8444 and demonstrates that targeted therapy with an engineered IgM antibody can result in tumor penetration and target engagement within tumor tissue. Taken together, the biomarker and PK data support the use of IGM-8444 at a dose of 3 mg/kg or above for combination studies. The randomized Phase 1b is underway and evaluates the activity of FOLFIRI+bev +/- IGM-8444 in 2L mCRC. Citation Format: Genevive Hernandez, Sanela Bilic, Yinghui Guan, John So, Sabya Bhattacharya, Beatrice Wang, Maya Kotturi, Miho Oyasu, Melanie Desbois, Yuan Cao, Eric Humke, Sean Ahern, Angus Sinclair, Susanna Ulahannan, Vivek Subbiah, Merideth Pelster, Patricia Lorusso, Gerald Falchook, Judy Wang, Minal Barve, Jaspreet Grewal, Warren Chow, Jason Henry, Michael Cecchini, Chris Takimoto, Maya Leabman. Pharmacokinetics and pharmacodynamics of IGM-8444, a first-in-class engineered pentameric DR5-targeting agonist IgM monoclonal antibody, in patients with R/R and newly diagnosed cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A137.

Abstract A032: Antitumor activities of different RIG-I agonists in a murine model of kidney adenocarcinoma

Abstract Purpose: Activation of retinoic acid-inducible gene I (RIG-I) signaling induces tumor cell apoptosis and enhances NK, dendritic, and effector T cell activity. We applied two distinct RIG-I agonists: purified influenza virus RNA (IV RNA) in combination with an agonistic OX40 receptor-specific monoclonal antibody (anti-OX40) and a 3p-hpRNA (5' triphosphate hairpin RNA) combined with unmethylated CpG oligonucleotide (CpG). We also investigated the CpG and anti-OX40 combination. The study aimed to establish the efficacy of these compounds in a murine model of kidney adenocarcinoma (Renca). Methods: Renca cells were subcutaneously engrafted in 40 BALB/c mice. The animals were allocated into three treatment groups and a control group. Intratumoral administration of specific adjuvant combinations was carried out thrice as follows: Group 1: CpG+anti-OX40, Group 2: CpG+3p-hpRNA, Group 3: IV RNA+anti-OX40, and Group 4: PBS. Daily monitoring encompassed assessment of primary tumor sizes and physiological parameters. Deceased mice underwent dissection, and histological evaluations were performed. Treatment efficacy was ascertained based on tumor growth, distant metastases' occurrence, and cytokine levels' alterations. Statistical analysis was conducted, with p-values&amp;lt;0.05 considered statistically significant. Results: On day 38 post-implantation, the survival rates for the various groups were as follows: Group 4: 20%, Group 1: 70% (sig), Group 2: 50% (ns), and Group 3: 60% (sig). Measurements of primary tumor sizes were conducted following the final treatment on day 17 and subsequently every seven days until day 38. On day 17, no significant disparities in primary tumor sizes were observed between Groups 1, 2, 3, and 4. However, on day 24, Groups 1, 2, and 3; on day 31, Groups 1 and 2 exhibited significantly smaller primary tumors than Group 4. By day 38, no significant differences in tumor sizes were evident among the groups. Notably, discernible variations in primary tumor characteristics were observed: Groups 1, 2, and 3 demonstrated incipient demarcation, whereas Group 4 exhibited diffuse primary tumors accompanied by necrosis. Concerning metastatic development, the results are currently under evaluation and will be available for presentation at the conference, alongside the outcomes of cytokine ELISA tests. Discussion: After concluding the experiment, we deem the treatments to hold considerable promise. Notably, while the treatment effects were sustained, tangible outcomes were achieved: prolonged survival of the mice, reduction in primary tumor sizes, and mitigated metastatic formation. However, following the final treatment, there was a notable decline in the animals' overall quality of life. Consequently, we decided to terminate the experiment. In light of our findings, we ascertain that the treatments serve as a solid foundation for further exploration. By modifying the composition of the treatment cocktails and adjusting the treatment frequency, there exists the potential for further enhancement of the achieved results. Citation Format: Dominik Gulyás, Márta Lőrincz, István Jankovics, Béla Dénes, Dóra Földi, Rhiannon Rodgers, Katie Commins, Gábor Andócs, Gábor Kovács. Antitumor activities of different RIG-I agonists in a murine model of kidney adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr A032.

Ascomylactam C Induces an Immunogenic Cell Death Signature via Mitochondria-Associated ER Stress in Lung Cancer and Melanoma.

Ascomylactam C (AsC) is a new 13-membered-ring macrocyclic alkaloid, which was first isolated and identified in 2019 from the secondary metabolites of the mangrove endophytic fungus Didymella sp. CYSK-4 in the South China Sea. AsC has been found to have a broad-spectrum cytotoxic activity. However, the antitumor effects in vivo and mechanisms of AsC remain unclear. The aim of this study was to describe the effects of AsC on lung cancer and melanoma cells and to explore the antitumor molecular mechanism of AsC. In vitro, we used plate colony formation experiments and demonstrated the ability of AsC to inhibit low-density tumor growth. An Annexin V/PI cell apoptosis detection experiment revealed that AsC induced tumor cell apoptosis. In vivo, AsC suppressed the tumor growth of LLC and B16F10 allograft significantly in mice, and promoted the infiltration of CD4+ T and CD8+ T cells in tumor tissues. Mechanistically, by analyses of Western blotting, immunofluorescence and ELISA analysis, we found that AsC increased ROS formation, induced endoplasmic reticulum (ER) stress, activated the protein kinase RNA-like ER kinase (PERK)/eukaryotic translation initiation factor (eIF2α)/activating transcription factor 4 (ATF4)/C/EBP homologous protein (CHOP) signaling pathway, and induced immunogenic cell death (ICD) of tumor cells. Our results suggest that AsC may be a potentially promising antitumor drug candidate.