Strategy For Cancer Treatment Research Articles

Abstract C033: Identifying and targeting prostate cancer therapy resistance mechanisms driven by the tumor microenvironment

Abstract Background: Prostate cancer is a prevalent malignancy in men, with treatment resistance posing a significant challenge to successful cure. Acquired Resistance to Therapy (ART) arises from two main components: (1) Tumor Microenvironment (TME) and (2) mutations or epigenetic changes at gene level within the tumor cells themselves. While most cancer therapies target the intrinsic biology of cancer cells, growing evidence indicates that these treatments can also harm the stromal cells within TME, potentially driving ART. The biology of ART may vary based on the types of treatments, cell types, and organ locations. Thus, this study aims to dissect ART components driven by TME-mediated cellular processes in a comprehensive manner. Hypothesis: We propose that cancer therapies induce stress responses in non-cancerous cells within the TME. These stress responses involve the secretion of cytokines, mediators, and growth factors, which we term Stress Response Secretory Programs (SRSPs). We further hypothesize that targeting SRSPs could overcome ART that helps to improve treatment specificity and efficacy. Materials and Methods: We employed comprehensive single-cell profiling of common metastatic sites included liver, prostate, lung, bone, lymph node and spleen in preclinical models to identify secreted proteins and dysregulated pathways caused by genotoxic therapies. In vitro, we evaluated treatment resistance in murine prostate epithelial cell lines (Myc-CAP) by exposing them to conditioned media (CM) from irradiated murine fibroblasts (F4M2), using cell growth assays. Results: Single-cell RNA sequencing of organ samples revealed significant expressions of SRSPs and increased inflammatory responses in liver and prostate fibroblasts as well as other stromal cells treated with carboplatin. In vitro, CM from irradiated F4M2 cells enhanced cell proliferation and survival of Myc-CAP cells in response to docetaxel treatment. Conclusion: Our findings highlight the crucial role of SRSPs in mediating ART through interactions within the TME, which alter tumor cell phenotypes. Targeting these SRSPs holds potential for overcoming treatment resistance and improving therapeutic outcomes, underscoring the need to consider TME complexity in cancer treatment strategies. Citation Format: Tony Lok Heng Chu, Armand Bankhead, Ilsa Coleman, Sander Frank, Peter S. Nelson, Tarana Arman. Identifying and targeting prostate cancer therapy resistance mechanisms driven by the tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C033.

MicroRNA-mediated autophagy and drug resistance in cancer: mechanisms and therapeutic strategies.

This paper provides an exhaustive overview of the intricate interplay between microRNAs (miRNAs) and autophagy in the context of human cancers, underscoring the pivotal role these non-coding RNAs play in modulating autophagic pathways and their implications for cancer development, progression, and resistance to therapy. MiRNAs, as critical regulators of gene expression post-transcription, influence various biological processes, including autophagy, a catabolic mechanism essential for cellular homeostasis, stress response, and survival. The review meticulously delineates the mechanisms through which miRNAs impact autophagy by targeting specific genes and signaling pathways, thereby affecting cancer cell proliferation, metastasis, and response to chemotherapy. It highlights several miRNAs with dual roles, acting either as oncogenes or tumor suppressors based on the cellular context and the specific autophagic pathways they regulate. The paper further explores the therapeutic potential of targeting miRNA-autophagy axis, offering insights into novel strategies for cancer treatment through modulation of this axis. Emphasizing the complexity of the miRNA-autophagy relationship, the review calls for more in-depth studies to unravel the nuanced regulatory networks between miRNAs and autophagy in cancer, which could pave the way for the development of innovative therapeutic interventions and diagnostic tools.

Carotenoids as modulators of the PI3K/Akt/mTOR pathway: innovative strategies in cancer therapy.

Cancer progression is primarily driven by the uncontrolled activation of cellular signaling pathways, with the PI3K/Akt/mTOR (PAMT) pathway playing a central role. This pathway significantly contributes to the proliferation and survival of cancer cells, and its hyperactivity is a major challenge in managing several types of malignancies. This article delves into the promising potential of carotenoids, natural pigments found in abundance in fruits and vegetables, as a novel therapeutic strategy for cancer treatment. By specifically targeting and inhibiting the PAMT pathway, carotenoids may effectively disrupt the growth and survival of cancer cells. The article examines the complex mechanisms underlying these interactions and highlights the obstacles faced in cancer treatment. It proposes a compelling approach to developing therapies that leverage natural products to target this critical pathway, offering a fresh perspective on cancer treatment. Further research is essential to enhance the therapeutic efficacy of these compounds.

Clinical advances and challenges in targeting FGF/FGFR signaling in lung cancer.

Fibroblast growth factors (FGFs) and their receptors regulate numerous cellular processes, such as metabolism and signal transduction, but can also drive tumorigenesis. Specifically, in lung cancer, the overexpression of FGFs, as well as the amplification, mutation and fusion of FGFR genes, are closely linked to the initiation, progression and resistance of the disease, suggesting that targeting FGF/FGFR is an attractive therapeutic strategy for lung cancer treatment. Nintedanib, a multitarget tyrosine kinase inhibitor (TKI) used in combination with docetaxel, has shown some success as a second-line therapy for lung cancer. However, clinical trials evaluating other FGFR inhibitors have yielded mixed results, indicating substantial complexity in targeting aberrant FGF/FGFR signaling. In this review, we describe the aberrations in FGF/FGFR signaling in lung cancer and summarize the clinical efficacy of FGFR inhibitors, such as multitarget TKIs, selective FGFR-TKIs and biological agents. We also discuss various challenges associated with FGFR targeting in lung cancer, including precision patient selection, toxicity and resistance. Finally, we provide perspectives on future directions, namely, developing novel FGFR-targeting drugs, such as FGFR degraders and more specific FGFR-TKIs, adopting combination therapy and targeting FGFs.

OGC SO15 - Utility of radiological re-staging following neo-adjuvant chemotherapy and its impact on oncological outcomes in resectable gastric adenocarcinoma

Abstract Background The current perioperative chemotherapy regimen that comprises the multimodal treatment strategy for gastric cancer consists of Fluorouracil, Leucovorin, Oxaliplatin, and Docetaxel. Despite improvement in outcomes at a population level, real-world data suggests that ≤40% of patients show a poor/no response to the neoadjuvant phase of treatment. Identification of these poor/non-responders may facilitate a re-evaluation of their treatment strategy and prevent potentially futile surgery. Radiological re-staging following neoadjuvant treatment is routinely performed despite its debatable accuracy and benefits. This study aimed to define the accuracy of radiological re-staging and its impact on survival following neoadjuvant treatment for resectable GC. Method Patients with resectable gastric cancer who completed 4 cycles of neoadjuvant FLOT and underwent resectional surgery with curative intent between 2018 and 2022 were retrospectively identified. All patients were clinically staged with gastroscopy, CT and staging laparoscopy. The index radiological/clinical stage at diagnosis was compared to the radiological re-staging following neoadjuvant treatment. Patient were re-staged with either a CT or PET-CT. Both were then compared with the final pathological stage to assess for correlation between the radiological and pathological stage. A survival analysis was then performed to evaluate the impact of radiological-pathological staging discrepancy on overall survival Results A total of 65 consecutive patients met the inclusion criteria of this study. On comparison of the index clinical stage with the radiological re-stage post-neoadjuvant treatment, 71% had concordant stages, 25% were downstaged, and 4% were upstaged. On comparison of the index clinical stage with the final pathological stage, 35% had concordant stages, 38% were upstaged and 27% were down staged (Cohen kappa = -0.224, 95% CI -0.390, -0.058). Discrepancy between clinical stage and radiological re-stage did not influence survival. However, discrepancy between clinical and pathological stage highlighted survival differences where upstaged patients had reduced survival (p = 0.018). Conclusion The accuracy of clinical staging compared to final pathological staging in the setting of aggressive tumour biology remains undefined. Radiological re-staging following neoadjuvant treatment proves to be an unreliable tool for assessing treatment response and does not predict long-term survival outcomes. These findings highlight the importance of accurate staging and the need for more precise methods of evaluating treatment response. This may enhance decision-making, individualise treatment regimens, and improve patient outcomes.

HPB O03 - Snapshot Audit of RELEVANCE: REal worLd outcomEs of adjuVant therapy in pANcreatic CancEr

Abstract Background Evidence-based medicine plays a critical role in shaping clinical practices and setting patient expectations. While randomized controlled trials (RCTs) of adjuvant chemotherapy in pancreatic cancer have demonstrated improved survival rates with newer regimens, their selective inclusion criteria often favor patients with better prognoses. This study aims to compare real-world outcomes with those from RCTs to evaluate the effectiveness of adjuvant therapies in typical clinical settings. Method In this retrospective study, we examined overall survival (OS) among patients who received adjuvant chemotherapy (gemcitabine, gemcitabine-capecitabine, or FOLFIRINOX) following the resection of pancreatic ductal adenocarcinoma. We compared survival curves from RCTs (ESPAC 4, PRODIGE-24) with those from real-world cohorts selected based on RCT criteria. Data were collected retrospectively from medical records and institutional databases, covering OS, disease-free survival (DFS), and adverse events. Results From July 2014 to December 2019, 303 pancreatic ductal adenocarcinoma patients underwent resections, with 209 (69%) receiving adjuvant chemotherapy: 91 (44%) received gemcitabine, 69 (34%) gemcitabine-capecitabine, and 37 (18%) FOLFIRINOX. The median OS for gemcitabine was 21.6 months, close to ESPAC 4’s 25.5 months. Gemcitabine-capecitabine had a median OS of 25.2 months versus ESPAC 4’s 28 months. FOLFIRINOX had a lower median OS in our cohort (19.9 months) compared to PRODIGE 24’s 54.4 months. Additionally, gemcitabine OS in PRODIGE 24 was higher (35 months) than in our data. FOLFIRINOX had a 17% completion rate. Conclusion The real-world outcomes for gemcitabine-based adjuvant therapy align closely with RCT results, while FOLFIRINOX appears less effective in typical clinical settings, possibly due to tolerance issues. These findings highlight the importance of incorporating real-world data in clinical decision-making to better predict patient outcomes and improve treatment strategies for pancreatic cancer. Further research is needed to bridge the gap between RCTs and real-world practices, especially concerning patient selection and treatment tolerability.

New strategies for lung cancer diagnosis and treatment: applications and advances in nanotechnology.

Lung cancer leads in causing cancer-related mortality worldwide, continually posing a significant threat to human health. Current imaging diagnostic techniques, while offering non-invasive detection, suffer from issues such as insufficient sensitivity and the risks associated with radiation exposure. Pathological diagnosis, the gold standard for confirmation, also faces challenges like invasiveness and high costs. In treatment, surgery, radiotherapy, and chemotherapy are the main modalities, each encountering challenges related to precision, environmental adaptability, and side effects. Nanotechnology's advancement provides new solutions for the diagnosis and treatment of lung cancer, promising to enhance diagnostic accuracy and reduce side effects during treatment. This article introduces the main types of nanomaterials used in the field of lung cancer, offering a comprehensive overview of current research on the application of nanotechnology in early screening, diagnosis, treatment, and monitoring of lung cancer, and summarizing ongoing clinical research findings.

Abstract A004: Full spectrum isolation technique-based dual circulating rare cells analysis to maximize early cancer diagnosis

Abstract Liquid biopsy (LB) is essential in precision medicine, enabling real-time tumor monitoring through repeated sampling. However, its diagnostic sensitivity and accuracy are limited by the low detection rate of circulating tumor cells (CTCs). For example, in breast cancer, the CTC detection rate exhibited only 20%, significantly limiting its clinical utility. This limitation arises since existing technologies selectively isolate specific phenotypes of CTCs, failing to capture others, such as mesenchymal CTCs, which are associated with poor prognosis. These mesenchymal CTCs often evade detection due to their lack of EpCAM expression and high deformability, making difficult to isolate them with traditional filter or EpCAM based methods. Additionally, conventional LB methods fail to provide critical insights into the tumor microenvironment (TME). To overcome these limitations, we developed a novel approach that improves LB diagnostic sensitivity and accuracy by (1) creating a technology to isolate all types of CTCs, regardless of marker expression or size, and (2) simultaneously analyzing CTCs and circulating cancer-associated fibroblasts (cCAFs). This dual approach addresses the challenges of low sensitivity and accuracy by enabling the isolation of a broader range of CTCs, including mesenchymal types, and by incorporating cCAF analysis. cCAFs, derived from the TME and found in the bloodstream, provide valuable insights into the TME that are hard to obtain through traditional methods. Analyzing cCAFs alongside CTCs offers a more comprehensive understanding of tumor biology and its microenvironment, leading to improved diagnostic accuracy, especially in early-stage cancer. In our study involving 55 breast cancer patients, we demonstrated that while CTCs were undetectable in 42.9% of early-stage patients, cCAFs were detected in all cases and were found to be 10 times more abundant than CTCs. Importantly, for the first time, this study uncovers that the diverse CAF subtypes previously identified in tissue samples also exist in the bloodstream, highlighting their critical role in providing TME-related insights. In addition, cCAF subtypes vary with hormonal receptor expression, and their marker analysis allows for 80.9% accurate classification of breast cancer subtypes. We applied this approach to early-stage breast cancer patients, for whom diagnosis through liquid biopsy is particularly difficult, and found that the combined analysis of CTCs and cCAFs achieved a 18% improvement in accuracy, with the AUC increasing from 0.6817 to 0.8009 compared to CTC analysis alone. This innovative approach significantly enhances LB by simultaneously isolating all CTC subtypes and incorporating cCAF analysis, thereby offering a more sensitive and accurate diagnostic tool. Beyond improving breast cancer diagnostics, this method has the potential to be applied to other tumor types and could also prove valuable for prognosis prediction and therapeutic response monitoring, ultimately leading to better patient outcomes and more effective cancer treatment strategies. Citation Format: Hyeongjung Woo, Simon A Joosse, Frederike Harten, Felix Hilpert, Klaus Pantel, Minseok S. Kim. Full spectrum isolation technique-based dual circulating rare cells analysis to maximize early cancer diagnosis [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr A004.

Small but mighty: Platelets as multifunctional architects of tumor metastasis and immune regulation

AbstractPlatelets play an irreplaceable role in hemostasis and wound healing. However, beyond these classical roles, as the smallest anucleate cells in the blood stream, they are crucial for immune response which have inflammatory functions through specialized receptors and different signaling pathways, influencing both innate and adaptive immune response. Furthermore, many research have proved that platelets significantly contribute to tumor metastasis and are associated with poor prognoses in cancer patients through its coagulability and supporting an immunosuppressive tumor microenvironment. When tumor cells detach from the primary tumor mass and enter the bloodstream, they rapidly initiate the direct activation and adhesion of platelets, forming a protective microenvironment. This environment shields circulating tumor cells (CTCs) from the mechanical shear forces of blood flow and immune surveillance. Here we delve into the interaction between platelets and immunomodulation and explore the multifaceted roles and underlying mechanisms by which platelets influence tumor cell metastasis and tumor growth. Furthermore, we also discussed the diagnostic role of platelets in cancer occurrence and progression, as well as the feasibility and prospects of targeting platelets for antitumor immunotherapy. This review provides a multidimensional perspective and reference for platelet‐related cancer treatment strategies and diagnosis.

Investigation of the efficacy of siRNA-mediated KRAS gene silencing in pancreatic cancer therapy

Aim Pancreatic carcinoma is an aggressive cancer that progresses without many symptoms. The difficulty of early diagnosis and an inadequate response to traditional treatments also cause the survival rate of pancreatic cancer to be low. Current research is focusing on methods of diagnosis and treatment, such as gene therapy, to increase survival rates. Small interfering ribonucleic acid (siRNA) has emerged as a promising advanced therapeutic strategy for cancer treatment. This study sought to silence the KRAS gene in the human pancreatic carcinoma cell line using a complex of small interfering ribonucleic acid (siRNA) and gold nanoparticles (AuNP). Methods In this study, 25 nM siRNA and gold nanoparticles at 0.5 mg/ml, 0.25 mg/ml, and 0.125 mg/ml concentrations were used to silence the KRAS gene in the CAPAN-1 cell line. Real-time PCR analysis, agarose gel electrophoresis, and double staining were carried out, and xCelligence real-time cell analysis (RTCA) was used to measure proliferation. Results The PCR analysis revealed crossing point (CP) values of actin beta (ACTB) ranging from 33.04 to 35.98, which was in the expected range for all samples. The interaction between the gold nanoparticle/siRNA complex in the double staining analysis revealed that the most effective concentration of gold nanoparticle was 0.125 mg/ml. The WST-1 technique showed that siRNA/AuPEI cells in application groups had a viability rate of over 90%, indicating no toxicity or side effects. The xCELLigence RTCA® showed that at hour 72, there was a significant difference in proliferation in the 0.5 mg/mL PEI/AuNP-siRNA, 0.25 mg/mL PEI/AuNP-siRNA, and 0.125 mg/mL PEI/AuNP-siRNA application groups compared to the control and siRNA groups (p < 0.05). By hour 96, all three groups were statistically different from the control and siRNA groups in terms of proliferation (p < 0.05). Conclusions The results of this analysis suggest that the AuPEI/siRNA complex can be effectively used to silence the target gene, but more studies are needed to verify these results.

EXTH-22. TARGETING MITOCHONDRIAL PROTEASE IN DIFFUSE GLIOMAS

Abstract BACKGROUND Targeting mitochondrial function has emerged as a promising therapeutic strategy in cancer treatment. TR107 is characterized as a specific activator of caseinolytic protease proteolytic subunit (ClpP) in the mitochondria, potentially affecting oncogenic pathways. Here, we investigated the effects of TR107 on adult malignant gliomas, IDH-wildtype and IDH-mutant METHODS We utilized patient-derived glioma cells to determine the efficacy of TR107 with cell viability, proliferation, cell cycle, and apoptosis assays. Immunofluorescent staining and electron microscopy (EM) were employed to uncover organelle morphological changes upon treatment. Mitochondrial function and ATP production were assessed in live cells utilizing Seahorse analysis. Global proteomics and RNA sequencing were performed to identify treatment-induced dysregulated pathways in glioma cells RESULTS Both IDH-wildtype and IDH-mutant glioma cell lines were highly sensitive to TR107, showing at least 100 times lower IC50 compared to the related compound ONC201. Genetic knock out of ClpP revealed that the growth inhibitory effects of TR107 are ClpP-dependent. Interestingly, IDH-mutant cell lines showed a more profound disintegration of mitochondrial morphology and dysregulation of mitochondrial function evidenced by an enhanced suppression of oxidative phosphorylation, mitochondrial complexes expression, mtDNA copy number, complex I activity, and ATP production, compared to IDH-wildtype cells. Six days of treatment with TR107 led to a complete inhibition of cell growth and up to 97% of cell death in IDH-mutant cells, while 50% of IDH-wildtype cells remained viable. Western blot, EM, and RNAsequencing analyses uncovered autophagy as a potential pro-survival mechanism in IDH-wildtype cells. Importantly, multiple metabolic and DNA repair-related pathways were affected by the treatment, suggested by global proteomics and RNA sequencing. Finally, TR107 was not affected by ABC transporters, supporting its potential use in brain tumor patients CONCLUSION TR107 demonstrated potent cytotoxic effects in patient-derived glioma cells by disrupting mitochondrial structural and functional integrity. TR107 efficacy in vivo is under investigation.

State-of-the-art therapy and innovative treatment strategies in esophageal squamous cell cancer

SummaryRecent advances in the development of new therapeutic agents and the execution of numerous randomized controlled trials have changed the landscape of systemic therapy approaches in patients with esophageal squamous cell cancer (ESCC). Particularly the inclusion of immunotherapy permits clinicians to improve patient management in multiple settings. This review gives an overview of standard-of-care treatment and sheds light on new therapeutic options, recently approved treatments, and ongoing trials.

Integrin-Specific Stimuli-Responsive Nanomaterials for Cancer Theranostics

Background: Cancer is one of the leading causes of death worldwide. The tumor microenvironment makes the tumor difficult to treat, favoring drug resistance and the formation of metastases, resulting in death. Methods: Stimuli-responsive nanoparticles have shown great capacity to be used as a powerful strategy for cancer treatment, diagnostic, as well as theranostic. Nanocarriers are not only able to respond to internal stimuli such as oxidative stress, weakly acidic pH, high temperature, and the high expression of particular enzymes, but also to external stimuli such as light and paramagnetic characteristics to be exploited. Results: In this work, stimulus-responsive nanocarriers functionalized with arginine-glycine-aspartic acid (Arg-Gly-Asp) sequence as well as mimetic sequences with the capability to recognize integrin receptors are analyzed. Conclusions: This review highlights the progress that has been made in the development of new nanocarriers, capable of responding to endogenous and exogenous stimuli essential to combat cancer.

Dual targeting and bioresponsive nano-PROTAC induced precise and effective lung cancer therapy

Epigenetic regulation has emerged as a promising therapeutic strategy for lung cancer treatment, which can facilitate the antitumor responses by modulating epigenetic dysregulation of target proteins in lung cancer. The proteolysis-targeting chimera (PROTAC) reagent, dBET6 shows effective inhibition of bromodomain-containing protein 4 (BRD4) that exerts antitumor efficacy by degrading BRD4 via the ubiquitin-proteasome system. Nevertheless, the low tissue specificity and bioavailability impede its therapeutic effects and clinical translation on lung cancer treatment. Herein, we developed a type of dual targeting and bioresponsive nano-PROTAC (c R GD/L LC membrane/D S-P LGA/d B ET6, named RLDPB), which was constructed by using the pH and glutathione (GSH)-responsive polymer, disulfide bond-linked poly(lactic-co-glycolic acid) (PLGA-S-S-PLGA, DS-PLGA) to load the PROTAC agent dBET6, and further camouflaged with the homotypic LLC cell membranes, followed by the conjugation with cRGD ligand to the surface of the nanoparticles. Notably, RLDPB showed enhanced celluar uptake by lung cancer cells in vitro and accumulation in the tumors via the dual targeting structure including cRGD and LLC membrane. The pH/GSH responsiveness improved the release of dBET6 from the DS-PLGA-based nanoparticles within the cells. RLDPB was demonstrated to facilitate tumor regression by inducing the apoptosis of lung cancer cells with the degradation of BRD4. Thus, RLDPB can be considered a powerful tool to suppress lung cancer, which opens a new avenue to treat lung cancer by PROTAC.Graphical abstract

The unexpected PD-L1 suppression function of celery-derived extracellular vesicles improves lung cancer chemotherapy efficacy

Aim: The article explores celery-derived extracellular vesicles (CDEVs), characterized by high cellular uptake, low immunogenicity, and high stability, as a therapeutic strategy for antitumor nanomedicines. Methods: The methods employed in this study include in vitro cell experiments such as co-culture, Western Blot, and flow cytometry. In vivo experiments were conducted in C57BL/6 tumor-bearing mice subcutaneously injected with Lewis lung carcinoma (LLC) cells. The experiments encompassed parameters such as survival rate, body weight, tumor size, flow cytometry, immunohistochemistry, and spectral live imaging system. Results: Our study revealed that CDEVs could be used as drugs to effectively downregulate the phosphorylated signal transducer and activator of transcription 3(p-STAT3)/programmed cell death ligand 1 (PD-L1) axis in lung cancer cells. In co-culture experiments, CDEVs were observed to impede the expression of PD-L1, thereby interfering with the interaction between PD-L1 and programmed death 1 (PD-1) and subsequently preventing the suppression of T cells. In in vivo distribution experiments, CDEVs loaded with paclitaxel (PTX) demonstrated better tumor targeting capabilities. Remarkably, following CDEVs-PTX treatment, CD8+ T cell levels in mice were increased, presumably leading to improved antitumor effects. Conclusion: CDEVs not only serve as drug carriers but also function as drugs themselves; as such, through a single administration of CDEVs, it is possible to combine immunotherapy and chemotherapy to achieve better effects between the two, providing a more comprehensive and effective cancer treatment strategy that promises to improve treatment outcomes and reduce the adverse effects of therapy.

Facile fabrication of dasatinib laden multifunctional polymeric micelles: Evaluation of anti‐proliferative and apoptotic activities in human cancer cells

AbstractDasatinib (DAS) has recently gained significant interest for its anticancer potential. Yet, the lipophilicity inherent in DAS limited its potential use as a chemotherapeutic drug. This study aimed to examine the effectiveness of polyethylene glycol‐polycaprolactone (PEG‐PCL) as a nanocarrier for DAS to increase its anticancer capabilities. The DAS‐loaded PEG‐PCL nanoparticles (termed as DAS@PEG‐PCL NPs) were characterized using Fourier transform infrared (FTIR), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and dynamic light scattering (DLS). Morphological staining and MTT tests were employed to investigate drug‐loaded nanoparticles' apoptotic and anti‐proliferative effects. The MTT assay demonstrated that incorporating DAS onto PEG‐PCL NPs resulted in a dose‐dependent increase in cytotoxicity in A549 (lung cancer) and HeLa (cervical cancer) cells. The A549 cancer cells were analyzed for their morphology using the acridine orange/ethidium bromide (AO/EB) and DAPI staining techniques. Overall, these findings demonstrate that the polymeric PEG‐PCL nanoparticle systems hold great potential as a novel therapeutic strategy for cancer treatment.

Precision Cancer Therapy Enabled Anti-Epidermal Growth Factor Receptor-Conjugated Manganese Core Phthalocyanine Bismuth Nanocomposite for Dual Imaging-Guided Breast Cancer Treatment.

Cancer remains a formidable global health challenge, demanding the exploration of innovative treatment modalities with minimized side effects. One promising avenue involves the synergistic integration of targeted photothermal/photodynamic therapy (PTT/PDT), utilizing specially designed functional nanomaterials for precise cancer diagnosis and treatment. This study introduces a composite biomaterial, anti-epidermal growth factor receptor-conjugated manganese core phthalocyanine bismuth (anti-EGFR-MPB), synthesized for precise cancer imaging and treatment. The biomaterial, synthesized via a solvothermal process, effectively treats and images breast cancer in mouse models. Its biomimetic design targets cancer cells precisely, with dual imaging for real-time monitoring. The biomimetic design of the composite enables precise targeting of cancer cells, whereas the dual imaging allows for real-time visualization and monitoring of the treatment. Invivo examinations confirm substantial damage to tumor tissues with no recurrence following 808-nm laser irradiation. The composite shows strong fluorescence/photoacoustic imaging (PAI) contrast, aiding malignancy detection. Biological assays and histological analyses confirmed the efficacy of the nanocomposite in inducing apoptosis in cancer cells. The integrated targeted dual image-guided phototherapy offered by this composite substantially enhances the precision and efficacy of cancer therapy, achieving an impressive photothermal efficiency of ~33.8%. Our findings demonstrate the utility of the anti-EGFR-MPB nanocomposite for both invitro and invivo photoacoustic image-guided PTT and PDT. The optimal treatment strategy for triple-negative breast cancer is found to be the use of 250 μg/ml of nanocomposite irradiated with 1.0 W/cm2 808-nm laser for 7 min.

Unraveling the role of exercise in cancer suppression: insights from a mathematical model

Recent experimental studies have shown that physical exercise has the potential to suppress tumor progression. Such suppression has been reported to be mediated by the exercise-induced activation of natural killer (NK) cells through the release of IL-6, a cytokine. Aimed at shedding light on how exercise-induced NK cell activation helps in the suppression of cancer, we developed a coarse-grained mathematical model based on a system of ordinary differential equations describing the interaction between IL-6, NK-cells, and tumor cells. The model is then used to study how exercise duration and exercise intensity affect tumor suppression. Our results show that increasing exercise intensity or increasing exercise duration leads to greater and sustained tumor suppression. Furthermore, multi-bout exercise patterns hold promise for improving cancer treatment strategies by adjusting exercise intensity and frequency. Thus, the proposed mathematical model provides insights into the role of exercise in tumor suppression and can be instrumental in guiding future experimental studies, potentially leading to more effective exercise interventions.

Assessment of Optimal Treatment Strategies and Their Outcomes in T3N1 Rectal Cancers.

Background:This study compares the outcomes of a surgery first vs a neoadjuvant treatment strategy in T3N1M0 rectal cancers. Methods:This was a single-centre retrospective cohort study of patients admitted for curative treatment of T3N1 rectal cancer. Patients with pre-treatment T3N1 and pathological T3N1 disease were included in the study. Patients were divided into two groups depending on whether they had surgery or neoadjuvant therapy as their initial phase of treatment. Primary outcome measures were local recurrence and distant recurrence. Secondary outcomes were disease-free survival (DFS) and overall survival (OS). Tabulated results were analyzed with appropriate statistical tests. Results:One hundred and ten patients were initially selected. Fourty-eight were finally included after excluding patients who did not meet the staging criteria or were not eligible for curative treatment. Twenty-nine patients underwent surgery, and 19 patients with neoadjuvant therapy as their first treatment. No local recurrence was noted in either group, with a distant recurrence noted in group 2 (6.9%) and group 1 (5.26%) cases among the surgery-first and neoadjuvant-first groups, respectively. Disease-free survival and overall survival were 29.5 and 30 months for the surgery-first group and 22 and 22 months for the neo-adjuvant group, respectively. Conclusions:Outcomes in the surgery-first group were non-inferior to that of the neoadjuvant group. A threatened circumferential resection margin (CRM) on pretreatment staging warrants neoadjuvant therapy to ensure an R0 resection. Extramural vascular invasion (EMVI), being a negative prognostic factor, doesn't preclude a surgery-first approach.

Synergistic effect of the sphingosine kinase inhibitor safingol in combination with 2'-nitroflavone in breast cancer.

Sphingosine kinase-1 (SPHK1), the enzyme that catalyzes the synthesis of the pro-oncogenic molecule sphingosine-1-phosphate, is commonly upregulated in breast cancer cells and has been linked with poor prognosis and progression by promoting cell transformation, proliferation, angiogenesis, and metastasis. Therefore, SPHK1-targeting drugs have been proposed for breast cancer treatment, with better antitumor results when they are combined with chemotherapy. Previously, we demonstrated that the synthetic flavonoid 2'-nitroflavone (2'NF) exerted a potent and selective antiproliferative effect in murine HER2-positive LM3 mammary tumor cells. As we found that these cells overexpress SPHK1, we decided to explore the antitumor action of the combination of SPHK inhibitors (safingol or SKI-II) with 2'NF. In vitro assays showed that the combination induced a synergistic antiproliferative effect in LM3 cells. Similar results were obtained when human HER2-positive MDA-MB-453 breast cancer cells were treated with the combination of 2'NF/safingol. We also found that safingol potentiated the 2'NF apoptotic effect in both cell lines. The synergistic antitumor effect was confirmed in vivo in an LM3 syngeneic breast cancer model. Moreover, western blot analysis of tumor lysates revealed that combined treatment increased PARP cleavage and Bax protein levels and decreased anti-apoptotic Bcl-xL and Bcl-2 protein levels. Additionally, mice treated with both compounds showed no histopathological effects on different organ tissues. In summary, these findings suggest that the combination safingol/2'NF can be proposed as a potential therapeutic strategy for HER2-positive breast cancer treatment. KEY MESSAGES: The combination safingol/2'-nitroflavone exerts a synergic antitumor action in vitro. Safingol potentiates 2'-nitroflavone apoptotic effect in breast cancer cells. Safingol enhances the 2'-nitroflavone antitumor activity in vivo in breast cancer.