bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of drug and non-drug interactions in patients treated in medical oncology.
Authors: Ghomari Yacine-Abdallah , Guendouz Souaad , Soumeyya Ghomari 
Published: June 2023

e15110 Background: Oncology patients frequently get multiple medications, including herbal supplements and medicines (chemotherapy, supportive care, comorbidities drugs, self-medication). This might pose a serious risk for drug interactions (DI) and non-drug interactions (NDI), which could endanger the patient's health. Our aims are to characterize the interactions, describe the risks to the patient they pose, and suggest a course of action to be followed. Methods: To make a pharmaceutical validation of chemotherapy prescriptions, this prospective study—the first of its kind at the national level—was carried out at the level of the Medical Oncology Department of CHU-Tlemcen from November 2021 to February 2022. It included patients treated on an outpatient basis who were receiving chemotherapy and/or targeted therapy. Following a medication reconciliation interview, patients from our sample who are being treated for one or more comorbidities are chosen in order to detect DIs using two French platforms (Vidal, Theriaque) and one Anglo-Saxon platform (Drugs). Hedrine was utilized to detect NDIs. Results: A total of 76 patients were enrolled for chemotherapy pharmaceutical validation. 36 (47%) of them were interviewed (median age = 61 years [42-86], sex ratio = 0,2), had at least one comorbidity treatment and 16 patients (45%) had breast cancer. The most frequently used protocols were anthracyclines (10 patients; 28%), anthracycline-taxanes (5 patients; 14%), capecitabine (5 patients; 14%), and capecitabine-oxaliplatin (3 patients; 8%). Seven patients (19%) used herbal supplements, primarily black seed ( Nigella sativa L.). Forty different interactions were listed for Vidal (23 precautions for use, 18 to be considered), 4 involved a chemotherapy drug. Forty-seven interactions with Theriaque (7 new interactions that Vidal missed, including 5 undesirable associations due to the use of ethanol as an excipient with a notable effect), 8 were due to a chemotherapy drug. On Drugs, 102 interactions were observed (4 serious, 90 moderated, and 8 minor), 38 involved a chemotherapeutic agent. Most interactions necessitated clinical and/or biological patient monitoring. In terms of NDIs, Hedrine indicates possible interactions by cross-referencing the effects of different plants on the organism with those of drugs, without giving any indication of the level of risk, what to do in case of risk. This makes interpretation difficult and requires expert opinion to guide action. No serious events were reported in the study. Conclusions: It is worthwhile to continue the pharmaceutical interview, especially for those most at risk for drug interactions, i.e., the elderly and/or patients on multiple medications. To widen the scope of interaction detection, it should be carried out prior to the recommendation of chemotherapy and refreshed when a patient's protocol changes utilizing at least one French and one Anglo-Saxon database.
Continuous dosing of AUM001 with cyclical gemcitabine/nab-paclitaxel to maintain the tumor growth kinetics in KPC xenograft model.
Authors: Chowbay Balram , Leong Wai Fook , Lee Sze Sing , Lim Jyue Yuan , Vidergar Romana , Tai Wai Meng David , Biswas Subhra Kumar 
Published: June 2023

e15112 Background: PDAC is a highly desmoplastic and aggressive disease with limited therapeutic options and poor 5-year survival outcome. Gemcitabine (GEM) plus nab-paclitaxel (nPTX) is widely used as a first line treatment for PDAC but advancement for greater improvement on efficacy is still warranted. Dysregulated mRNA translation of pro-tumorigenic genes has contributed to the proliferative and metastatic nature of PDAC. Targeting oncogenic mRNA translation via MNK-coupled phosphorylation of eIF4E could serve as a target for inhibition to synergize chemotherapy. AUM001 is a novel MNK1/MNK2 inhibitor undergoing clinical trials in various solid tumors. We hypothesize that combination of AUM001 with GEM-nPTX would have synergistic effect in modulating the tumor growth kinetics and maintaining the tumor in a stable state. Methods: PDAC KPC cells were subcutaneously implanted into BL6 mice and randomized into five treatment groups once tumor volumes of 60-80mm3 were reached. Saline (control), GEM-nPTX were administered intraperitoneally on days 1, 4 and 8 while AUM001 was given orally on a daily basis for 8 days. The combination of GEM-nPTX and AUM001 were administered at similar doses and frequency. AUM001 was given for another 3 weeks in the continuous dosing group. Body weight and tumor volume were measured thrice weekly. Immunohistochemistry staining was performed on FFPE sections for Ki67, angiogenesis and stromal markers. Apoptosis was analyzed by Annexin V-propidium iodide flow cytometric assay. P < 0.05 was considered as statistically significant. Results: GEM-nPTX and AUM001 (GPA) or GEM-nPTX (GP) alone resulted in approximately 30% reduction in relative tumor volume. The continuous dosing of AUM001 (GPAc) after the cessation of chemotherapy showed a marked 55% decline in relative tumor volume ( P= 0.0079) compared to GPA. The phosphorylation of EIF4E (target of MNK1/2) and Myc expression were significantly inhibited in GPAc vs GPA groups at end of observation (EOO) (P < 0.05). VEGFA expression at EOO was found to be suppressed in GPAc compared to GPA group ( P= 0.0159) with no difference in MVD ( P> 0.05). Greater fraction of apoptotic cells was detected in GPAc at EOO ( P= 0.055) than GPA ( P> 0.999) when referenced to GP group. Conclusions: This study demonstrated that continuous dosing of AUM001 with cyclical GEM-nPTX is well-tolerated and confers good anti-tumor effect. Pharmacodynamic analysis also suggests that AUM001 may potentiate the reduction in pro-tumorigenic protein expression. This is the first study depicting the continuous dosing of AUM001 after cessation of chemotherapy could help to maintain the tumor state, facilitating its possible use in clinics as maintenance therapy in PDAC.
Preclinical evaluation of novel HER3-targeting radioconjugates for the imaging and treatment of HER3-expressing cancers.
Authors: Beckford Vera Denis , Li Jason , Xu Le-Cun , Lewis Debbie , Chin Amanda , Brodin Patrik , Chen Mary , Roy Monideepa , Kotanides Helen 
Published: June 2023

e15114 Background: HER3 overexpression in tumors is associated with poor survival and is implicated in drug resistance mechanisms of HER1 (EGFR) and HER2 targeted therapies. Although antibodies against HER3 have been developed and evaluated in clinical trials, no HER3 targeted therapy has been approved, underscoring the unmet need for novel HER3 therapeutic approaches. We hypothesized that HER3 radioligand targeted therapies could provide enhanced therapeutic efficacy against HER3-positive cancers through the energy deposited by alpha or beta emitting radionuclides in tumor cells. Here we describe the development and preclinical evaluation of novel anti-HER3 antibody radioconjugates (ARCs), 225Ac-HER3 and 177Lu-HER3, using the alpha-emitting Actinium-225 (225Ac) and beta-emitting Lutetium-177 (177Lu) radioisotopes, respectively. Methods: ARCs were prepared by radiolabeling HER3 antibody with 225Ac or 177Lu using S-2-(4-Isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (p-SCN-Bn-DOTA) to yield 225Ac or 177Lu-HER3-ARCs. DOTA modified antibodies were characterized by HPLC and MALDI-TOF and HER3-ARCs were fully characterized by instant thin-layer chromatography (iTLC) and HPLC. The in vitro binding properties of the HER3-ARCs were evaluated using HER3 recombinant proteins and cells expressing HER3 in ELISA and flow cytometry. The in vivo pharmacological properties of the HER3-ARCs were evaluated by molecular imaging using Zirconium-89 (89Zr) Positron Emission Tomography (PET), biodistribution and antitumor efficacy studies. Results: HER3 antibody was successfully modified with p-SCN-Bn-DOTA to yield a conjugate with approximately 8 DOTAs per antibody molecule. Results from the in vitro binding assays of ARCs to either HER3 human recombinant protein or cells expressing HER3 demonstrated similar binding properties of 225Ac-HER3 and 177Lu-HER3 to unmodified HER3 antibody. The biodistribution study in NCI-H1975 tumor bearing mice showed that both 225Ac-HER3 and 177Lu-HER3-ARCs specifically accumulate in HER3-expressing tumors relative to other tissues. In agreement with the biodistribution studies, PET images revealed specific uptake of 89Zr-HER3 in NCI-H1975 tumors. Furthermore, 225Ac and 177Lu-HER3-ARCs showed significantly more potent NCI-H1975 tumor growth inhibition compared to controls. Conclusions: Our findings suggest that a HER3 targeted radiotherapy approach can enhance therapeutic response and overcome the limitations of previously explored HER3 targeted drug modalities. Thus, further preclinical evaluation of 225Ac-HER3 and 177Lu-HER3 is warranted, including in settings of tumor drug resistance, which can provide the basis for investigating HER3-ARCs as an effective treatment approach in future clinical trials.
A novel 89Zr-a-PD-1 immuno-PET-CT may improve pseudoprogression detection in a lung cancer murine model receiving immunotherapy.
Authors: Puyalto Calvo Ander , Rodríguez-Remírez María , Lopez Ines , Iribarren Fabiola , Torregrosa Maria , Simon Jon Ander , Ecay Marga , Collantes Maria , Vilalta Anna , Francisco-Cruz Alejandro , Solorzano Jose Luis , Peñuelas Ivan , Ajona Daniel , Gil-Bazo Ignacio 
Published: June 2023

e15116 Background: Immune checkpoint inhibitors (ICIs) have revolutionized lung cancer treatment improving survival outcomes of non-small cell lung cancer (NSCLC) patients. Response assessment of patients on ICIs treatment represents a challenge since an increase in tumor size or the appearance of new lesions might not reflect true disease progression (P) but pseudoprogression (PP), which has been reported in a range of 3-6% in NSCLC. Conventional 18F-FDG-PET scans do not accurately discriminate P from PP. We have recently reported the efficacy of a combined blockade of PD-1 and ID1 in NSCLC mouse model. We aimed to evaluate a novel 89Zr-labelled radiotracer for micro mPET-CT to detect PP in a NSCLC murine model. Methods: Syngeneic subcutaneous tumors were generated using LLC cells (with constitutive expression of ID1 or ID1-silenced) in C57BL6J and in ID1-deficient mice, treated with PBS or with a commercially available monoclonal antibody against PD-1 (a-PD-1) (RPM1-14, 300 mg, IP, on days 7, 10 and 14). Tumor growth and response to ID1-PD-1 blockade, was measured by 18F-FDG uptake. Additionally, PP was measured labelling the anti-PD-1 with 89Zr (89Zr-a-PD-1) and analyzing 89Zr uptake at day 15, 17 and 20. Tumor microenvironment was analyzed with immunohistochemistry, multiplex immunofluorescence and quantification of relative expression of interleukins by RT-PCR. Results: 18F-FDG uptake did not show significant differences between groups, underestimating the real metabolic response induced by the treatment. However, 89Zr-mPET-CT showed a significantly higher 89Zr uptake when ID1 was inhibited in both, tumor cells and tumor micro-environment and mice were treated with a-PD-1 (p = 0.0075). The analysis of the tumor tissues in those animals by immunohistochemistry and multiplex immunofluorescence disclosed an increase in immune T CD8+ cells infiltration, being responsible for the antitumor response observed and correlating with 89Zr signal. Moreover, the analysis of interleukins expression showed that tumors with ID1 inhibition in the tumor micro-environment presented an upregulation of pro-inflammatory interleukins, favoring T- cell infiltration. Conclusions: ID1 inhibition in tumor cells and in tumor micro-environment combined with PD-1 blockade enhanced immune cell infiltration through pro-inflammatory interleukins upregulation. 89Zr-a-PD-1 immuno-PET-CT may improve PP detection in a NSCLC murine model receiving immunotherapy.
Antitumor activity of AX-0085, a novel AXL kinase inhibitor: Analysis of apoptotic cell death in triple-negative breast cancer cells.
Authors: Choi Myeong Jun , Woo SangHyeon , Kim DongHa , Janardhan Keshav Karapurkar , Yoon SungIl , Park Young Jun , Kim Jaesang , Jang Jun Young , Han Byung Woo , Suresh Ramakrishna , Kim Kye-Seong 
Published: June 2023

e15120 Background: Triple-negative breast cancer (TNBC) is insensitive to targeted therapies due to the negative expression of human epidermal growth factor receptor-2, estrogen receptor and progesterone receptor. TNBC cells express higher levels of AXL more often than other breast cancer subtypes. The receptor tyrosine kinase AXL plays a role in survival, invasion, migration, epithelial-mesenchymal transition (EMT), metastasis, resistance, and immune suppression in cancer cells including in TNBC. Thus, AXL is a promising therapeutic target for the treatment of TNBC, and we developed a new small-molecule AXL inhibitor, AX-0085. Methods: The interaction mechanism between AX-0085 and AXL was studied by molecular dynamic simulations, cell-based kinase assay, and western blotting in TNBC cells. We investigated the anti-tumor activity of AX-0085 on the AXL-dependent pro-tumorigenic properties such as cell proliferation, invasion, migration, EMT, and immune suppression (PD-L1 expression) in TNBC cell lines and investigated in vivo efficacy of AX-0085 with the 4T1 xenograft model. Results: In the molecular dynamic simulations, estimated binding energy of AX-0085 and cabozantinib to AXL was -10.1Kcal/mol and -8.1Kcal/mol, respectively. AX-0085 was made a hydrogen bond with catalytically important residue Lys567 and blocked the activation of AXL by inhibiting the salt bridge with Lys567-Glu585. AX-0085 (IC50: 4.4nM for AXL kinase in cell-based kinase assay) was one of the most potent AXL inhibitors. AX-0085 showed a high antitumor activity against all TNBC subtypes and was a more potent anti-proliferative activity than other kinase inhibitors in MDA-MB-231 cell line. AX-0085 effectively blocked the activation of AXL in TNBC and further inhibited AXL-dependent pro-tumorigenic events such as cell proliferation, invasion, migration, EMT, and PD-L1 expression in TNBC cell. AX-0085 induced cell cycle arrest at G1 phase and suppressed the expression of CDK2 and Cyclin E in TNBC. AX-0085 promoted apoptotic cell death by up-regulating cleaved caspase-9 and down-regulating Bcl-2 in TNBC. Pharmacological investigation showed that the AX-0085 treated tumors displayed a dose-dependent reduction in volume and weight of the tumors in the 4T1 mouse xenograft. Conclusions: Our results demonstrated that AX-0085 selectively blocks AXL activation which confers an effective therapeutic value in the treatment of TNBC. Currently, AX-0085 is undergoing non-clinical trials.
Tumor sensitization to PARP inhibitors by DNA damaging synthetically lethal acylfulvenes.
Authors: Kulkarni Aditya , Zhou Jianli , Bhatia Kishor , Sharma Panna 
Published: June 2023

e15123 Background: 20-30% of solid tumors (ovarian, breast, pancreatic, prostate cancers) harbor some level of deficiency in DNA Damage Repair (DDR) pathways. Such cancers become dependent on alternative DDR pathways to maintain genome integrity, making them selectively vulnerable to DNA damaging agents. The concept of synthetic lethality has been leveraged to treat subsets of such tumors. Clinically, PARP inhibitors (PARPi) have been successful in Homologous Recombination Deficiency (HRD) cancers. LP-100 and LP-184 are acylfulvene (AF) class small molecule prodrugs that are metabolized to active compounds by prostaglandin reductase 1 (PTGR1) that is often elevated in solid tumors. AF-induced DNA lesions are likely selectively processed by repair pathways including BRCA1/2 mediated Homologous Recombination (HR). Methods: Cell Titer Glo based 10 day cell viability assays were used to generate drug IC50 values in vitro. Bliss synergy scores were computed with scores ≥ 10 reflecting synergy. Drug-induced DNA double strand breaks (DSB) were detected and quantified with STRIDE (SensiTive Recognition of Individual DNA Ends) assay in cancer cells. A subcutaneous tumor xenograft model was used to determine tumor volumes in control and drug treated mice. Results: In a BRCA2 mutant ovarian cancer cell line OVCAR3, LP-184 and olaparib co-treatment in vitro showed synergistic effects (Bliss score 10). Similarly in a BRCA2 mutant prostate cancer cell line 22Rv1, LP-100 combination with rucaparib was synergistic (Bliss score 18). 400 nM LP-184 showed a time dependent increase in DNA DSB signals in vitro, 1.7X more so in BRCA2 mutant vs wild type (WT) DLD-1 isogenic colon cancer cell lines up to 24 hours. To validate the hypothesis that AF-induced DSBs remain unresolved if exposed to and further synergize with PARPi in vivo, we tested LP-100 plus olaparib in a DU145 (BRCA2 mutant) prostate cancer xenograft model. LP-100 + olaparib treatment resulted in sustained, durable tumor regression indicating in vivo synergy whereas either agent alone did not produce tumor shrinkage. Day 42 tumor growth inhibition was 66% for 2.5 mg/kg LP-100 alone, 34% for 40 mg/kg olaparib alone and 108% for the combination. Moreover, LP-184 treatment resulted in early onset and complete tumor regression in 7 PDX models of PARPi resistant triple negative breast cancers (TNBC) harboring BRCA1/2 loss whereas olaparib/ niraparib remained entirely ineffective in these. Conclusions: AF response is influenced by tumor DNA repair competence. LP-100 and LP-184 are synthetically lethal resulting from their abilities to cause unresolvable DNA damage where tumor cells express high PTGR1 and are deficient in the HR pathway. LP-184 single agent was superior to PARPi in TNBC and LP-100 combination made an olaparib resistant tumor highly sensitive, thereby facilitating a path to extend the opportunities for both AFs and PARPis and enhance the clinical utilization of PARPi.
The effect of adding a selective FAK inhibitor AMP945 to FOLFIRINOX in a model of pancreatic cancer.
Authors: Burns Christopher , Murphy Kendelle , Cock Terrie-Anne , Devlin Mark , Herrmann David , Timpson Paul 
Published: June 2023

e15128 Background: Pancreatic Cancer (PC) is a one of the leading causes of cancer-related death in the world, with a five-year survival rate of ~11%. The majority of patients present with advanced metastatic disease and are treated with chemotherapy. FOLFIRINOX is the standard-of-care treatment for patients in many countries and has been shown to result in a median overall survival of 11.1 months. Focal Adhesion Kinase (FAK) is a non-receptor tyrosine kinase which transduces signaling from integrin receptors, activated through interactions with the extracellular matrix, to regulate cell survival, proliferation and migration, and is often highly expressed in PC. Inhibition of FAK in preclinical models of PC has been shown to sensitize cells to radiotherapy, immunotherapy and chemotherapy. AMP945 is a potent and selective FAK inhibitor currently undergoing a Phase Ib/IIa trial in PC in combination with gemcitabine and nab-paclitaxel (NCT05355298). We now demonstrate that AMP945, in combination with FOLFIRINOX, can significantly improve survival in mouse models of PC, providing strong rationale for clinical testing of this novel treatment combination. Methods: Patient Derived Xenograft (PDX) models of PC in NOGIL2 mice using TKCC10lo patient derived cells were conducted in both subcutaneous and orthotopic formats. Once the tumor was palpable, AMP945 (10 mg/kg, b.i.d.) was administered for four days. On day 8 oxaliplatin (5 mg/kg) and irinotecan (25 mg/kg) were administered, with leucovorin calcium (100 mg/kg) and fluorouracil (25 mg/kg) being dosed on day 9. The mice were monitored until day 12 and the treatment regimen was repeated for up to 20 cycles, or until the experimental endpoint was reached. At the experimental endpoint the mice were sacrificed, the tumor harvested and analyzed. Results: In the subcutaneous model the combination of AMP945 and FOLFIRINOX increased survival by ~35% compared to FOLFIRINOX alone. In the orthotopic model, median survival was extended by ~30% when using the AMP945/FOLFIRINOX combination, compared to FOLFIRINOX alone. In both models there was a significant reduction in tumor size and clear evidence of on-target FAK inhibition in tumors (reduction in pY397FAK levels) in the combination therapy groups. Notably, a significant increase in cleaved caspase-3, a marker of apoptosis, was also apparent in the combination therapy groups. Conclusions: The FAK inhibitor AMP945, given in a pulsed-dosing regimen in combination with FOLFIRINOX, significantly enhances survival in a mouse model of pancreatic cancer by increasing apoptosis and reducing tumor burden, highlighting the potential of this combination in clinical treatment of PC. A clinical study of the combination of AMP945 with FOLFIRINOX is now in planning.
Penpulimab combined with anlotinib therapy in patients with advanced refractory solid tumors: A single-center, observational, prospective study.
Authors: Zhou Shansi , Wang Tao 
Published: June 2023

e15129 Background: Antiangiogenesis therapy combined with PD-1/PD-L1 inhibitors has shown excellent efficacy in advanced refractory solid tumors. In advanced NSCLC patients,this conclusion has been confirmed in a number of clinical studies such as WJOG@Be Study and JVDF. A clinical study, KEYNOTE-524/Study116, demonstrated survival benefits from this combination model in liver cancer, and a similar trend was seen in patients in the bile duct cancer study presented.Penpulimab + anlotinib is an important combination immunotherapy. Here we described the results of safety, and clinical efficacy of penpulimab combined with anlotinib in patients with advanced solid tumors, the serum cytokine levels, and peripheral blood T lymphocyte populations were detected simultaneously. Methods: 17 cases with advanced cancers including lung, gallbladder, cholangiocarcinoma, and hepatocellular Carcinoma were treated since January 2022. Patients received a combination of anlotinib (12mg) once daily on day 1 to day 14 (21days as a course) plus anti-PD-1 antibodies every 3 weeks until progression or intolerabletoxicity. Imaging was performed every 6 weeks for thefirst year of therapy. Blood samples were collected from patients prospectively. Serum interleukin (IL-2, IL-4, IL-6, IL-10), tumornecrosis factor-α(TNF-α), interferon-γ(IFN-γ) and circulating immune cell subsets were measured at baseline and after two cycles of treatment via flow cytometry. Results: From January 2022 to December 2022, 17 patients had received the combination therapy of penpulimab plus anlotinib (median age 68.8yrs [range 51-83],52.9% males, 100% ECOG PS 1. Most patients had received frist line treatments for metastatic disease (82.4%). Of 13 pts who have had at least one tumor assessment, the ORR（objective remission rate ）was 35.29% (6 PRs) and DCR was 58.82% (4 SDs). The median PFS was 7.98 months (95% CI: 1.68-NE months).Up to now, eight responders remain in response.The most common adverse reactions included：hypertension was 1/17（5.9%）, Hand foot syndrome was 1/17（5.9%）, loss of appetite was 1/17（5.9%）.There were no grade 3 and above treatment-related adverse events. Conclusions: The combination of penpulimab plus anlotinib as a treatment for advanced refractory solid tumor showed the promising efficacy with a manageable safety profile, thereby suggesting that this combination therapy may be a viable treatment strategy for advanced refractory solid tumor patients.