Cancer Therapy Research Articles

Activatable Photosensitizers: From Fundamental Principles to Advanced Designs

Photodynamic therapy (PDT) is a promising treatment that uses light to excite photosensitizers in target tissue, producing reactive oxygen species for localized cell death. It is recognized as a minimally invasive, clinically approved cancer therapy with additional preclinical applications in arthritis, atherosclerosis, and infection control. A hallmark of ideal PDT is delivering disease‐specific cytotoxicity while sparing healthy tissue. However, conventional photosensitizers often suffer from non‐specific photoactivation, causing off‐target toxicity. Activatable photosensitizers have emerged as more precise alternatives, offering controlled activation. Unlike traditional photosensitizers, they remain inert and photoinactive during circulation and off‐target accumulation, minimizing collateral damage. These photosensitizers are designed to “turn on” in response to disease‐specific biostimuli, enhancing therapeutic selectivity and reducing off‐target effects. This review explores the principles of activatable photosensitizers, including quenching mechanisms stemming from activatable fluorescent probe and applied to activatable photosensitizers (RET, PeT, ICT, ACQ, AIE), as well as pathological biostimuli (pH, enzymes, redox conditions, cellular internalization), and bioresponsive constructs enabling quenching and activation. We also provide a critical assessment of unresolved challenges in aPS development, including limitations in targeting precision, selectivity under real‐world conditions, and persistent issues and potential solutions (dual‐lock, targeting moieties, biorthogonal chemistry and artificial receptors).

Activatable Photosensitizers: From Fundamental Principles to Advanced Designs.

Photodynamic therapy (PDT) is a promising treatment that uses light to excite photosensitizers in target tissue, producing reactive oxygen species for localized cell death. It is recognized as a minimally invasive, clinically approved cancer therapy with additional preclinical applications in arthritis, atherosclerosis, and infection control. A hallmark of ideal PDT is delivering disease-specific cytotoxicity while sparing healthy tissue. However, conventional photosensitizers often suffer from non-specific photoactivation, causing off-target toxicity. Activatable photosensitizers have emerged as more precise alternatives, offering controlled activation. Unlike traditional photosensitizers, they remain inert and photoinactive during circulation and off-target accumulation, minimizing collateral damage. These photosensitizers are designed to "turn on" in response to disease-specific biostimuli, enhancing therapeutic selectivity and reducing off-target effects. This review explores the principles of activatable photosensitizers, including quenching mechanisms stemming from activatable fluorescent probe and applied to activatable photosensitizers (RET, PeT, ICT, ACQ, AIE), as well as pathological biostimuli (pH, enzymes, redox conditions, cellular internalization), and bioresponsive constructs enabling quenching and activation. We also provide a critical assessment of unresolved challenges in aPS development, including limitations in targeting precision, selectivity under real-world conditions, and persistent issues and potential solutions (dual-lock, targeting moieties, biorthogonal chemistry and artificial receptors).

Tocotrienols in Eleven Species of Hypericum Genus Leaves

Saint John’s worts or goatweeds are mostly perennial flowering plants in the Hypericaceae family, formerly under the Clusiaceae family. Teas and macerations of the plants are common in traditional medicines and modern depression and cancer therapies. The most notable bioactive compounds in Hypericum are hyperforin and hypericin. While Hypericum contains a variety of carotenoid and phenolic compounds, which are well documented, there is little available information on tocopherols and almost none on tocotrienols. Considering the frequency of tocotrienol derivatives in Clusiaceae species, this study investigates and reports the presence of tocotrienols in eleven Hypericum species’ leaves: H. hircinum, H. hookerianum, H. calycinum, H. xylosteifolium, H. densifolium, H. prolificum, H. kalmianum, H. frondosum, H. olympicum, and two hybrids: H. × moserianum and H × ‘Rowallane’. Eight tocopherol and tocotrienol forms (α, β, γ, δ) were detected in the leaves, predominantly containing α-tocopherol. Tocotrienol content was most significant in Myriandra section species and was highest in H. prolificum (22.90 ± 0.63 mg 100 g−1), while the highest tocotrienol proportion was observed in H. × ‘Rowallane’ (54.12% of total tocochromanols) and H. prolificum (37.27% of total tocochromanols). The results demonstrated significant tocochromanol accumulation in Hypericum leaves.

Rational Design of Metal-Organic Frameworks for Pancreatic Cancer Therapy: from Machine Learning Screening to In Vivo Efficacy.

Despite improvements in cancer survival rates, metastatic and surgery-resistant cancers, such as pancreatic cancer, remain challenging, with poor prognoses and limited treatment options. Enhancing drug bioavailability in tumors, while minimizing off-target effects, is crucial. Metal-organic frameworks (MOFs) have emerged as promising drug delivery vehicles owing to their high loading capacity, biocompatibility, and functional tunability. However, the vast chemical diversity of MOFs complicates the rational design of biocompatible materials. This study employed machine learning and molecular simulations to identify MOFs suitable for encapsulating gemcitabine, paclitaxel, and SN-38, and identified PCN-222 as an optimal candidate. Following drug loading, MOF formulations are improved for colloidal stability and biocompatibility. In vitro studies on pancreatic cancer cell lines have shown high biocompatibility, cellular internalization, and delayed drug release. Long-term stability tests demonstrated a consistent performance over 12 months. In vivo studies in pancreatic tumor-bearing mice revealed that paclitaxel-loaded PCN-222, particularly with a hydrogel for local administration, significantly reduced metastatic spread and tumor growth compared to the free drug. These findings underscore the potential of PCN-222 as an effective drug delivery system for the treatment of hard-to-treat cancers.

Hyaluronic acid regulated facile synthesis of size-tunable multifunctional nanomedicine for effective cancer therapy.

The complex and heterogeneous nature of cancer necessitates the development of innovative multifunctional nanomedicines (MN). Hyaluronic acid (HA) is a functional carbohydrate polysaccharide that is widely used in various biomedical fields. In this study, we employed HA as a stabilizer and regulator for the synthesis of a size-tunable nanomedicine comprising ferric ions, doxorubicin, and epigallocatechin gallate (EGCG), referred to as HDE-MN, for cancer therapy. A change in the HA ratio can yield HDE-MNs with sizes varying from ~20nm to over 100nm. Modified HA can respond to hyaluronidase (HAase) to provide controllable pH/HAase dual-responsive drug release for improved cancer therapy. Moreover, HA can mediate the targeted delivery of HDE-MNs both in vitro and in vivo to cancer cells. In addition, HDE-MNs reversed multidrug resistance owing to the incorporation of EGCG, inducing ferroptosis due to the involvement of ferric ions. More importantly, HDE-MNs have a photothermal conversion effect, enabling photothermal therapy, photothermally enhanced drug release, and ferroptosis, which collectively contribute to significantly improved cancer therapy. Therefore, the HDE-MNs with laser irradiation achieved full ablation of the in vivo tumors. Together with its good biocompatibility, HDE-MNs may be promising for effective cancer therapy.

Navigating PROTACs in Cancer Therapy: Advancements, Challenges, and Future Horizons.

Proteolysis Targeting Chimeras (PROTACs) have revolutionized cancer therapy by offering a selective and innovative approach to degrade key oncogenic proteins associated with various malignancies. These hybrid molecules exploit the ubiquitin-proteasome system, facilitating the degradation of target proteins through an event-driven mechanism, thereby overcoming drug resistance and enhancing selectivity. With diverse targets including androgen receptors, BTK, estrogen receptors, BET proteins, and BRAF, PROTACs offer a versatile strategy for personalized cancer treatment. Advantages of PROTACs over traditional small molecule inhibitors include their ability to operate at lower concentrations, catalyzing the degradation of multiple proteins of interest with reduced cytotoxicity. Notably, PROTACs address challenges associated with traditionally "undruggable" targets, expanding the therapeutic landscape of cancer therapy. Ongoing preclinical and clinical studies highlight the transformative potential of PROTACs, with promising results in prostate, breast, lung, melanoma, and colorectal cancers. Despite their potential, challenges persist in optimizing physicochemical properties and enhancing bioavailability. Further research is needed to refine PROTAC design and address complexities in molecule development. Nevertheless, the development of oral androgen receptor PROTACs represents a significant milestone, demonstrating the feasibility and efficacy of this innovative therapeutic approach. This review provides a comprehensive overview of PROTACs in cancer therapy, emphasizing their mechanism of action, advantages, and challenges. As PROTAC research progresses, continued exploration in both preclinical and clinical settings will be crucial to unlocking their full therapeutic potential and shaping the future of personalized cancer treatment.

Little strokes fell big oaks: The use of weak magnetic fields and reactive oxygen species to fight cancer.

The increase in early-stage cancers, particularly gastrointestinal, breast and kidney cancers, has been linked to lifestyle changes such as consumption of processed foods and physical inactivity, which contribute to obesity and diabetes - major cancer risk factors. Conventional treatments such as chemotherapy and radiation often lead to severe long-term side effects, including secondary cancers and tissue damage, highlighting the need for new, safer and more effective therapies, especially for young patients. Weak electromagnetic fields (WEMF) offer a promising non-invasive approach to cancer treatment. While WEMF have been used therapeutically for musculoskeletal disorders for decades, their role in oncology is still emerging. WEMFs affect multiple cellular processes through mechanisms such as the radical pair mechanism (RPM), which alters reactive oxygen species (ROS) levels, mitochondrial function, and glycolysis, among others. This review explores the potential of WEMF in conjunction with reactive oxygen species as a cancer therapy, highlighting WEMFs selective targeting of cancer cells and its non-ionizing nature, which could reduce collateral damage compared to conventional treatments. In addition, synchronization of WEMF with circadian rhythms may further enhance its therapeutic efficacy, as has been demonstrated in other cancer therapies.

AGX101: A TM4SF1-directed tubulin inhibitor conjugate in ongoing first-in-human trial including GI cancers.

829 Background: TM4SF1 (Transmembrane-4 L-Six-Family-Member-1) is an endothelial marker with critical roles in angiogenesis, as well as a tumor cell antigen that contributes significantly to invasion and metastasis. TM4SF1 is upregulated 20-fold in angiogenic tumor vascular endothelium compared to normal vasculature endothelium and exhibits a unique nuclear internalization pathway. AGX101 is a novel tubulin inhibitor conjugate specifically directed against TM4SF1, delivering a potent maytansinoid payload directly to the nucleus of cells within the tumor microenvironment. Delivery to both the vascular and tumor cell compartments of the tumor results in three mechanisms of action (MoAs): (1) activation of tumor immune surveillance, (2) tumor blood supply deprivation, and (3) direct tumor cell killing. Methods: TM4SF1 expression was assessed using immunohistochemistry. Safety and pharmacokinetics of AGX101 were evaluated in non-human primates (NHP), with escalating doses to determine the highest non-severely toxic dose (HNSTD). Efficacy studies were also conducted in mouse models, enabling assessment of the minimum effective dose (MED) needed to engage each of the three MoAs. The combination of HNSTD and MED enables calculation of a therapeutic index (TI). The potential for synergy with immune checkpoint inhibitors (ICIs) was also investigated. A first-in-human study of AGX101 in patients with advanced solid tumors with the primary objective of safety and dose-limiting toxicities (DLTs) has initiated. Results: Notable cancers with high TM4SF1 scoring intensity include pancreatic adenocarcinoma, hepatocellular carcinoma, cholangiocarcinoma, and gastric cancer. In esophageal cancer, 20% of patients have a TM4SF1 copy number amplification, and these have worse prognosis. In NHP, AGX101 exhibited a favorable safety profile. In preclinical efficacy studies, monotherapy demonstrated robust efficacy through each of the three MoAs in syngeneic models in mice including CT26 colon carcinoma, and human tumor xenograft models including MIA PaCa-2 pancreatic cancer. Measured by exposure, TI was large. In syngeneic mouse models including CT26, the effects of ICIs were potentiated, suggesting a potential synergistic approach in cancer therapy. The first two dose levels of AGX101 monotherapy in humans has cleared without DLTs. Three patients with pancreatic adenocarcinoma have been treated thus far. Conclusions: AGX101, targeting the TM4SF1 antigen, represents a promising new approach in cancer therapy. The preclinical data suggest that AGX101 could provide a significant therapeutic benefit by novel and differentiated mechanisms of action, namely selectively targeting the tumor vasculature and potentiating immune-based therapies. Further clinical development of AGX101 is ongoing and initial outcome data will become available by the conference. Clinical trial information: NCT06440005 .

Long-course chemoradiation vs short-course radiation in total neoadjuvant therapy for rectal cancer: Propensity score case-matched analysis.

156 Background: Short-course radiotherapy (Short-TNT) is not widely used in the United States as part of total neoadjuvant therapy (TNT) for rectal cancer, due to concerns for lower tumor regression, increased local recurrence, and poorer quality of surgical specimens compared to long-course chemoradiotherapy (Long-TNT). However, there have been few studies that directly compared outcomes of Long-TNT versus Short-TNT. This study aimed to evaluate outcomes of Short-TNT versus Long-TNT. Methods: Consecutive patients with stage II-III rectal cancer who underwent TNT at an NCI-designated comprehensive cancer center from 2019 to 2022 were identified. Outcomes after Short-TNT and Long-TNT were compared using 1:1 propensity score matching. Results: Among 318 patients, 170 (85 Short-TNT, 85 Long-TNT) were eligible for the matched analysis (Table). The median follow-up was 31 months. The two groups were similar in tumor distance from anal verge (5cm vs. 6cm), clinical stage (stage III: 90.6% vs. 89.4%), radiologic high-risk features, and treatment sequence (induction chemotherapy: 30.5% vs. 28.2%). The Long-TNT was associate with a higher proportion of nonoperative management (38.8% vs. 24.7%, p=0.03). A local regrowth rate with long-TNT was not lower than short-TNT (39.4% vs. 28.6%, p=0.42). There were no differences in rates of clinical complete plus near-complete response (52.9% vs. 52.9%, p=1.00), overall complete response (pathologic plus sustained clinical complete response; 32.2% vs. 29.9%, p=0.74), and surgical outcomes including retrieved lymph nodes number (19 vs. 22, p=0.27), sphincter preservation (46.2% vs. 62.5%, p=0.10), distal margin (3cm vs. 3.5cm, p=0.77), CRM+ (83.8% vs. 3.1%, p=0.42) and postoperative complications (overall: 34.6% vs. 25.0%, p=0.14; ≥Grade3: 5.8% vs. 9.4%, p=0.60). Conclusions: Short-TNT had a comparable overall complete response rate with equivalent surgical outcomes to Long-TNT. Short-TNT should be revisited in the US as a viable alternative TNT strategy both for nonoperative management and for treatment of locally advanced rectal cancer. Propensity score case-matched analysis. Outcomes Total (n=170) Long-TNT (n=85) Short-TNT (n=85) p value Clinical complete/near complete response, number (%) 90 (52.9) 45 (52.9) 45 (52.9) 1.00 Non-operative management, number (%) 54 (31.8) 33 (38.8) 21 (24.7) 0.03 Overall complete response, number (%)* 54 (31.0) 26 (30.6) 28 (32.9) 0.74 Surgical outcomes Surgery (n=116) Surgery after Long-TNT (n=52) Surgery after Short-TNT (n=64) Sphincter-preserving surgery, number (%) 64 (55.2) 24 (46.2) 40 (62.5) 0.10 Circumferential resection margin +, number (%) 4 (3.4) 2 (3.8) 2 (3.1) 0.42 Distal margin, cm (range) 3.4 (0.1-12) 3 (0.2-6.5) 3.5 (0.1-12) 0.77 Major complications (≥Grade3), number (%) 9 (7.8) 3 (5.8) 6 (9.4) 0.60 *Pathologic + sustained clinical complete response.

Predictive Value of Magnetic Resonance Complete Response After Neoadjuvant Therapy for Rectal Cancer.

Previous research has demonstrated that after neoadjuvant therapy for rectal cancer, the sensitivity of magnetic resonance complete response (mrCR) for detecting pathologic complete response (pCR) in the surgical specimen ranges from 74 to 94%. Patient and provider interest in nonoperative management of rectal cancer that responds favorably to neoadjuvant therapy has grown, necessitating stronger evidence for how well radiographic complete response truly predicts pCR. We sought to determine the current association between mrCR and pCR in locally advanced rectal cancer. We conducted a retrospective cohort study of patients with rectal adenocarcinoma who underwent neoadjuvant chemoradiation followed by index proctectomy at a single academic referral center from January 2012 to December 2021. Our primary outcomes were mrCR, defined as the absence of residual disease on restaging MRI, and pCR, defined as the absence of residual adenocarcinoma in surgical pathology specimens. Among 523 eligible patients, 157 met the inclusion criteria (38.9% females; 51.0% nonwhite; mean [SD] age, 58.6 [13.2] years). Overall, 8.9% of patients had mrCR and 7.0% had pCR. The sensitivity and positive predictive value of mrCR were 36.4% (95% CI: 10.9 to 69.2) and 28.6% (95% CI: 8.4 to 58.1). Our findings were qualitatively unchanged when only patients in the last 5 years of the study period were included. Study limitations include that neoadjuvant therapy regimens were not standardized and patients who were offered and elected to undergo nonoperative management were not included. The value of mrCR in predicting pathologic response following neoadjuvant therapy in locally advanced rectal cancer is low, and mrCR should be interpreted with caution when counseling patients about nonoperative management. Early, frequent surveillance is critical in patients who elect nonoperative management after mrCR.

Factors and timing of decreased adherence to S-1 in postoperative docetaxel + S-1 therapy for gastric cancer.

403 Background: The combination of docetaxel + S-1 (DS) therapy in postoperative adjuvant treatment for gastric cancer has proven to be effective and has become a standard therapy. Clarification of factors involved in and the timing of S-1 non-adherence is important to minimize non-adherence. Methods: Among 92 patients who started DS treatment as postoperative adjuvant chemotherapy for gastric cancer between November 1, 2015 and April 30, 2021 at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 90 were eligible for this study. The S-1 adherence rate per cycle was defined as the number of times a patient took S-1 divided by 28. In this study, adherence to S-1 was assessed through pill counts and by asking patients about reasons for non-adherence in interviews at a pharmaceutical outpatient clinic. Elicited reasons for non-adherence were categorized and analyzed. Results: Percentage of remaining S-1 was 3.9% in the first cycle, 7.4% in the second cycle, and 2.0% in the seventh cycle. Median relative dose intensity of S-1 was 80.9%. As reasons for non-adherence, patients most commonly cited nausea/vomiting (18.9%), missed dose (17.6%), and diarrhea (9.9%). From the first to the seventh course, the highest percentage of remaining S-1 was in the second course. Conclusions: Nausea/vomiting, missed dose, and diarrhea were identified as the most common factors for decreased adherence to S-1 in postoperative DS therapy for gastric cancer. Between the first and seventh courses, S-1 adherence decreased the most during the second course, when docetaxel was started. Using this information, we intend to develop methods to improve S-1 adherence in the future.

A phase IIa clinical trial of first-line cyclical therapy alternating gemcitabine, cisplatin, and durvalumab with pemigatinib for advanced biliary tract cancers with FGFR2 -alterations.

TPS645 Background: Unresectable biliary tract cancer (BTC) has a poor prognosis. Frontline chemo-immunotherapy (C-IO) for advanced BTC leads to ~25% overall survival (OS) at 24-month, but 93-99% of patients reported adverse events (AEs), and 13-19% of patients stopped treatment drugs due to AEs. FGFR kinase inhibitors (FGFRi) are second-line therapy for 10% of BTC with FGFR2 fusions. However, clinical trials of upfront FGFRi have not accrued well. Cumulative toxicities frequently interrupt treatment and limit feasibility of concurrent C-IO + FGFRi. Over time, side effects from each of therapies have a negative impact on patients’ quality of life (QoL). We previously treated two FGFR2 -altered BTC patients with cyclical chemotherapy (CT) and FGFRi and observed prolonged survival with better QoL. By monitoring serial circulating tumor DNA (ctDNA), we observed development of FGFRi-resistant subclones while on FGFRi and their subsequent clearance after resuming CT. Thus, we have developed a clinical trial to validate our hypothesis that upfront cyclical therapy alternating between C-IO and FGFRi can improve therapeutic efficacy and QoL. Alternating therapy is hypothesized to avoid accumulating toxicities and treat emerging resistance subclones. Methods: In this single-center, single-arm, Phase IIa trial, all treatment-naive patients with FGFR2 -altered advanced BTCs, PS ≤ 1, are eligible. Patients will receive cyclical therapy alternating between two therapy-blocks, starting from C-IO block (2 cycles of gemcitabine, cisplatin and durvalumab, 28-day/cycle), then FGFRi block (3 cycles of pemigatinib on day 1-14 of 21-day/cycle). Block-switch continues until progressive disease (PD), and then we will continue alternated block until the next PD. A sample size of 30 is calculated based on an expected 12-month OS rate of ≥ 55%. The trial is anticipated to enroll the first patient in early 2025. Results: The primary objective is 12-month OS rate. Secondary objectives are overall response rate, progression-free survival, AEs. We will stratify patients to PD-L1 CPS <1 or ≥ 1 to assess if cyclical therapy can enhance IO. Exploratory objectives are (1) assessing dynamics of FGFR2 -ctDNA variants throughout therapy correlating with clinical outcomes, using a custom liquid biopsy (FGFR-Dx) developed at the Ohio State University; (2) assessing QoL scores with EORTC-QLQ-C30 and -BIL21 questionnaires, correlating with clinical outcomes. Results will be compared to historical controls from TOPAZ-1 trial. Conclusions: Cyclical therapy will be one of the first to combine alternating C-IO and targeted therapy in cancer. This strategy can be validated in other tumors if it is proven effective in our trial. Cyclical therapy holds great promise to introduce FGFRi earlier into treatment for BTC and improve both efficacy and QoL.

Supplying LSD1 with FAD in pancreatic cancer: A matter of protein-protein interaction?

Lysine-specific demethylase 1 (LSD1) is a key regulator in cancer epigenetic, and its activity is reliant on flavin adenine dinucleotide (FAD) as a cofactor. In this study, we investigated the correlation between LSD1 and FAD synthase isoform 2 (FADS2) protein levels in pancreatic ductal adenocarcinoma (PDAC) cell lines. We first assessed LSD1 protein and mRNA levels in mutant p53-expressing PANC-1 and MiaPaCa2 cells and p53-null AsPc-1cells, compared to human pancreatic ductal epithelial (HPDE) controls. Our results confirmed elevated LSD1 protein levels in PANC-1 and MiaPaCa2, but not in AsPc-1, despite mRNA overexpression across all cell lines. Similarly, FADS2 levels were significantly upregulated in PANC-1 and MiaPaCa2, but not in AsPc-1, highlighting a possible link between FADS2 expression and p53 gain-of-function mutations. These results prompted us to better investigate the functional relationship between FADS2 and LSD1 by performing in cellulo protein-protein interaction analyses. Our results indicate a direct interaction between LSD1 and FADS2, while no significant interaction was observed between LSD1 and FADS1. These findings reinforce the role of FAD synthesis and its delivery to LSD1 as critical events in cancer progression and shed light on potential implications of FADS2-LSD1 dynamics as targeted therapies in cancer.

Role of glutaminyl-peptide cyclo-transferase-like protein (QPCTL) in cancer: From molecular mechanisms to immunotherapy.

Glutaminyl-peptide cyclotransferase-like protein (QPCTL) is a newly discovered enzyme that has sparked interest owing to its possible role in cancer genesis and progression. Initially discovered as a post-translational modification regulator of protein maturation, QPCTL has emerged as a key participant in cancer biology. Recent research has linked QPCTL to numerous essential cancer-related processes, including cell proliferation, migration, invasion, and apoptosis. Furthermore, QPCTL expression changes have been seen in a variety of cancer types, underlining its potential as a diagnostic and prognostic marker. The molecular mechanisms behind QPCTL's participation in cancer will be examined in this review. We investigate its involvement in the control of signaling pathways and the modification of cellular activities that are important in cancer. We also examine the clinical importance of QPCTL, including as its relationship with tumor development, metastasis, and response to treatment. We also discuss the possible therapeutic implications of targeting QPCTL in cancer therapy. QPCTL is a prospective target for the development of innovative anticancer treatments due to its participation in several cancer-associated pathways.

Meta-analysis of randomized controlled trials (RCTs) to evaluate the incidence of hemorrhage and venous thromboembolism (VTE) events in patients with gastrointestinal (GI) cancers treated with fruquintinib.

118 Background: Fruquintinib is a novel cancer therapy that was recently approved by the US FDA as a third-line treatment for metastatic colorectal cancer (mCRC). It works by inhibiting the vascular endothelial growth factor receptors, that leads to blocking of angiogenesis which is essential for the tumor proliferation. Close monitoring is always crucial in order to promptly detect and manage any adverse events. This study aims to assess the risk of hemorrhagic and VTE events in patients with GI cancers treated with fruquintinib. Methods: A comprehensive literature search was conducted using MEDLINE, EMBASE, and COCHRANE databases from inception through August 12th, 2024. Phase II/III RCTs utilizing fruquintinib in GI cancers reporting hemorrhage or VTE events as an adverse event were included. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran’s Q-statistic. Random effects model was applied. Results: A total of 1872 patients were included. Data were pooled from three phase III RCTs (FRESCO, FRESCO-2, FRUTIGA) and one phase II RCT, all reporting VTE events including deep vein thrombosis and pulmonary embolism and hemorrhage. FRESCO, FRESCO-2, and the phase II trials involved patients with mCRC, comparing fruquintinib to placebo. FRUTIGA trial incorporated patients with gastric or gastroesophageal junction adenocarcinoma, comparing fruquintinib + paclitaxel to placebo + paclitaxel. High-grade hemorrhage incidence was higher in the fruquintinib arm compared to the control arm (29.00% vs 21.18%, RR 1.62; 95% CI: 1.26-2.08, P=0.0001). In the mCRC subgroup, high-grade hemorrhage rate was also higher and statistically significant in the fruquintinib arm 20.87% vs 11.22% (RR 1.84; 95% CI: 1.25-2.70; P=0.002). Incidence of any grade or high grade VTE events was neither statistically significant in GI cancer population or mCRC subgroup. Incidence of any grade VTE events in GI cancer group and mCRC subgroup was 2.74% vs 2.15% (RR, 1.23; 95% CI: 0.53-2.88; P=0.63) and 2.68% vs 1.53% (RR, 0.95; 95% CI: 0.09-9.67; P=0.97), respectively. Rate of high grade VTE events in GI cancer cohort was 1.67% vs 0.67% (RR, 1.96; 95% CI: 0.52-7.36; P=0.32), while in mCRC subgroup was 1.79% vs 0.76% (RR, 1.08; 95% CI: 0.06-19.98; P=0.96). Conclusions: This meta-analysis demonstrates that patients with GI cancers, including mCRC, treated with fruquintinib have higher incidence of high-grade hemorrhage. These findings underscore the importance of individualized risk assessment, especially for patients predisposed to hemorrhagic complications. No increased risk of VTE events was noted in patients treated with fruquintinib compared to placebo.

Meta-analysis of phase II/III randomized controlled trials (RCTs) to determine the incidence of hypertension and proteinuria in patients with gastrointestinal (GI) cancers treated with fruquintinib.

119 Background: Fruquintinib is a selective inhibitor of vascular endothelial growth factor receptors which impedes angiogenesis associated with tumor growth. On November 8th, 2023, the US FDA approved fruquintinib for use as a third-line treatment for metastatic colorectal cancer (mCRC). With the introduction of novel cancer therapies, monitoring for adverse events is critical. This meta-analysis aims to assess the risk of hypertension (HTN) and proteinuria in patients with GI cancers treated with fruquintinib. Methods: We conducted a comprehensive search of MEDLINE, EMBASE, and COCHRANE databases from inception through August 12th, 2024, identifying Phase II/III RCTs that employed fruquintinib in GI cancers and reported HTN and proteinuria as adverse effects. The Mantel-Haenszel method was used to calculate pooled risk ratios (RR) with 95% confidence intervals (CI). Heterogeneity was assessed using Cochran’s Q-statistic, and a random effects model was applied. Results: Our analysis included 1872 patients, 1131 (60%) of whom received fruquintinib, from three Phase III RCTs (FRESCO, FRESCO-2, FRUTIGA) and one Phase II RCT. FRESCO, FRESCO-2, and the phase II trials compared fruquintinib to placebo in patients with mCRC. FRUTIGA trial involved patients with gastric or gastroesophageal junction adenocarcinoma, comparing fruquintinib + paclitaxel to placebo + paclitaxel. The incidence of any-grade HTN was higher in the fruquintinib group, 34.92% vs 7.55% (RR 3.96; 95% CI: 3.05-5.13; P<0.00001); the rate of high-grade HTN was 13.96% vs 1.21% (RR 9.01; 95% CI: 4.67-17.40; P<0.00001). In the mCRC subgroup, incidence of any-grade and high-grade HTN was 43.02% vs 10.45% (RR 3.97; 95% CI: 2.95-5.33; P<0.00001), and 17.28% vs. 1.27% (RR 12.06; 95% CI: 5.19-28.01; P<0.00001), respectively. Incidence of any-grade proteinuria was also found to be statistically significant and higher in the fruquintinib arm in both GI cancer cohort and mCRC subgroup: 27.3% vs 16.19% (RR 1.89; 95% CI: 1.30-2.74; P=0.0008), and 25.22% vs 11.73% (RR 2.29; 95% CI: 1.17-4.51; P=0.02). The rate of high-grade proteinuria was not statistically significant in both cohorts. In GI cancer group, 1.85% vs 0.53% (RR, 2.49; 95% CI: 0.86-7.16; P=0.09), and mCRC subgroup 2.17% vs 0.51% (RR, 2.87; 95% CI: 0.74-11.12; P=0.13). Conclusions: This meta-analysis revealed a higher incidence of any-grade and high-grade HTN with fruquintinib in GI cancer patients, with significant association in the mCRC subgroup. Fruquintinib was also noted to be associated with increased risk of any-grade proteinuria, however, incidence of high-grade proteinuria was not different in patients treated with fruquintinib compared to placebo. Prompt identification and early management of these adverse events are crucial.

Design, synthesis, and biological evaluation of N1-(2-(adamantan-1-yl)-1H-indol-5-yl)-N2-(substituent)-1,2-dicarboxamides as anticancer agents targeting Nur77-mediated endoplasmic reticulum stress.

Targeting endoplasmic reticulum (ER) stress-induced apoptosis has attracted considerable research interest in anti-cancer drug development. Nur77 is a potential therapeutic target in many cancers and several Nur77 modulators have recently been identified as effective anticancer agents by activating ER stress. As an ongoing work, this study reports a new series of novel N1-(2-(adamantan-1-yl)-1H-indol-5-yl)-N2-(substituent)-1,2-dicarboxamides as potent Nur77 modulators that cause ER stress-induced apoptosis. Among this new series, most compounds show improved cytotoxicity against liver cancer (HepG2 and Huh7) and breast cancer (MCF-7 and MDA-MB-231) cell lines. The representative analog 15h dramatically induces Nur77 expression and cell apoptosis, showing excellent growth inhibition of HepG2 and MCF-7 cells (IC50<5.0μM). Mechanistically, 15h binds (KD=0.477μM) and activates Nur77-mediated ER stress through the PERK-ATF4 and IRE1 signaling pathways, thereby inducing cell apoptosis. In vivo, 15h treatment strongly suppresses HepG2 xenograft tumor growth (tumor shrink by 54.06%). In summary, we synthesize a series of novel indole derivatives, among which 15h has significantly improved pharmacological activity against various cancer cells. We further identify 15h as a novel ligand of Nur77, which may serve a therapeutic lead for developing new cancer therapy.

Updated trends in incidence and mortality of pancreatic cancer. an analysis of the Surveillance, Epidemiology, and End Results (SEER) database.

786 Background: Pancreatic cancer is the fourth leading cause of cancer deaths in the United States. The prognosis for pancreatic cancer remains poor despite advances in cancer therapy. In this study, we provide updated trends in pancreatic cancer incidence and mortality using the SEER database, with a subset analysis of age and gender. Methods: Using the SEER Stat software, we gathered data from the Surveillance, Epidemiology, and End Results (SEER) database (2000–2021). We employed Jointpoint regression to analyze the secular trend of incidence and incidence-based mortality (IBM), which we classified and arranged according to age and sex. Results: 235,116 cases met the inclusion criteria for our study. These included diagnosed cases of pancreatic cancer from 2000 to 2001. The total age-adjusted incidence rate was 12.5 per 100,000. 118,791 (50.5%) were males and 116,325 (49.5%) were female. While the annual percentage change (APC) from 2000-2019 was 0.92 (p &lt; 0.05), signifying an annual cumulative increase, APC from 2019-2021 was -0.085, signifying an annual cumulative decrease. For males, the APC was 0.94 (p &lt; 0.05) from 2000 to 2018 and -0.55 from 2018-2021, and for females, the APC was -0.89 (p &lt; 0.05) from 2019-2021. The pancreatic cancer IBM APC from 2000-2022 was 22.60 (p &lt; 0.05) and 0.54 (p &lt; 0.05) from 2002-2021. For males, IBM APC was 21.10 (p &lt; 0.05) from 2000-2002 and 0.58 from 2002-2021. For females, IBM APC was 25.15 from 2000-2002 and 0.42 from 2002-2021. We also studied pancreatic cancer IBM based on age. For 30-49 years, APC from 2000-2002 was 34.65 (p &lt; 0.05), and -0.64 (p &lt; 0.05) from 2002-2021. For 50-69 years, APC from 2000-2002 was 28.05 (p &lt; 0.05) and 0.3 from 2002-2021. For 70+ years, APC from 2000-2002 was 21.28 (p &lt; 0.05) and 0.73 from 2002-2021. Conclusions: There was a statistically significant rise in incidence and incidence-based mortality across the board, underscoring the need for improved diagnostic and therapeutic modalities of management of pancreatic cancer.

Promoting macrophage phagocytosis of cancer cells for effective cancer immunotherapy.

Cancer therapy has been revolutionized by immunotherapeutic agents exploiting adaptive antitumor immunity in the past two decades. However, the overall response rate of these immunotherapies is limited, and patients also develop resistance upon treatment, promoting a rapidly growing exploration of anti-tumor innate immunity for effective cancer therapy. Among these, macrophage immunotherapy through harnessing macrophage phagocytosis has been thrust into the spotlight due to its potential for simultaneously inducing cancer cell killing effect and mobilizing adaptive antitumor responses. Here in this review, we summarize the current macrophage immunotherapy such as therapeutic antibodies, phagocytosis checkpoint blockades, and CAR-macrophages with a particular emphasis on the resistant mechanisms limiting their therapeutic effects. Moreover, we further survey the efforts being placed to seek synergistic mechanisms and combination strategies for promoting macrophage phagocytosis which might stand as next-generation cancer immunotherapy.

Exploring Tephrosin: A review of its potential in cancer therapy and multifaceted anticancer mechanisms

Exploring Tephrosin: A review of its potential in cancer therapy and multifaceted anticancer mechanisms