bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of folate receptor-positive circulating tumor cells in the prognosis analysis of esophageal squamous cell carcinomas.
Authors: Zhou Qiang , He Qiao , Han Yongtao , Wang Dongsheng , Leng Xuefeng
Published: June 2024

e15026

Background: Patients with ESCC always be discovered at an advanced stage and have a poor prognosis. The Circulating Tumor Cells (CTCs) were investigated for use as a biomarker for diagnosis and assessing the effectiveness of treatment. This study aims to investigate the predictive value of the baseline level of folate receptor-positive circulating tumor cells (FR+CTCs) for disease-free survival (DFS) and overall survival (OS) in patients with esophageal squamous cell carcinomas (ESCC). Methods: A retrospective observational study was conducted from January 2018 to February 2021 and followed up to June 2022 with ESCC patients in Sichuan Cancer Hospital & Institute Esophageal Cancer Case Management Database (SCCH-ECCM Database). Three ml of peripheral blood were obtained from each patient, and FR+CTCs were quantified using ligand-targeted polymerase chain reaction (LT-PCR). Traditional techniques were employed to measure other serum markers. Clinicopathological features were collected from the hospital medical record system, and survival data (DFS and OS) were obtained by outpatient follow-up or phone calls. The correlation between clinicopathological characteristics, survival data, and FR+CTCs was analyzed. Cox regression analysis was used to assess risk factors that might have an impact on DFS and OS. Results: Analysis was conducted on 123 ESCC patients. Of them, 86% were men, and their average age was 62.0. FR+CTCs did not significantly correlate with patient age, sex, albumin, pre-albumin, C-reactive protein (CRP), ferritin, tumor size, grade of differentiation, metastasis of lymph nodes, perineural invasion/vessel invasion, or tumor size (all P>0.05). But for DFS (HR 3.29; 95% CI 1.52-7.15, P=0.003) and OS (HR 3.85; 95% CI 1.53-9.72, P=0.004), preoperative FR+CTCs were an independent prognostic factor. Patients with post-operative FR+CTCs ≥17.42 FU/3ml had a substantially shorter DFS than patients with FR+CTCs < 17.42 FU/3ml (P=0.0012). Patients with FR+CTCs ≥17.42 FU/3ml had a shorter OS than patients with FR+CTCs <17.42 FU/3ml, although the difference was not statistically significant (P=0.51). Conclusions: Patients with ESCC who have elevated FR+CTCs typically have a poorer prognosis. We anticipate that FR+CTCs will be able to guide clinical treatment, assess patient prognosis, and monitor cancer recurrence and metastasis in real-time.
Thioredoxin 1 in blood as a monitoring biomarker for patients with breast cancer post-treatment.
Authors: Kim Young , Ko Hye Mi , Lee Ye Ri , Suh Kyoung Hoon , Kim Je Ryong , Lee Jin Sun
Published: June 2024

e15041

Background: The spatial and temporal heterogeneity of tumors in breast cancer pose challenges in precision oncology. Although breast imaging during screening has increased tumor detection and reduced mortality rates, it is limited in tracking minimal residual disease after surgery. Consequently, there is a need for liquid biopsy with easy longitudinal sampling to track real-time changes in tumor characteristics during treatment. Existing biomarkers (CA15-3 and CEA) for post-treatment monitoring are unsatisfactory. This study explores the clinical validity and stability of thioredoxin1 (Trx1) in a 54-month longitudinal study, reflecting tumor characteristics during treatment. Methods: Approved by IRB from Chungnam National University Hospital (IRB: 2021-02-003). Fourteen out of the initial 20 BC patients were finally enrolled because pre-surgery samples for the 6 patients excluded were missing. A total of 116 sera were collected before and after surgery at intervals from 6 to 54 months. After isolating the serum, an immunoassay was performed to measure the level of serum Trx1 using the DxMe® BC kit (E&S Healthcare). CA15-3 and CEA levels were measured in paired samples and collected from medical records. The results were retrospectively analyzed along with clinical information, and the profile of Trx1 level change was analyzed for each individual. Results: The blood Trx1 levels in pre-operation BC patients were 20.68±4.44 U/ml (±SD). From 6 months’ post-operation to the 54th month, blood Trx1 levels in patients were consistently low, averaging 5.43±3.34 U/ml (p < 0.0001 compared to pre-op). In contrast, levels of CEA and CA15-3 did not change significantly before and after surgery. The pre-op and post-op AUC for Trx1, CA15-3, and CEA were 0.998 (95% CI: 0.941 to 1.000), 0.599 (95% CI: 0.482 to 0.709), and 0.550 (95% CI: 0.433 to 0.663), respectively. There was no significant difference in the decreasing profile of Trx1 levels over 54 months between different treatment methods. While existing a microscopic difference according to BC characteristics, all post-op values were already below the cut-off value. Regardless of treatment, Trx1 levels decreased to those of normal healthy women after surgery. There were no recurring cases to compare over 54 months. Conclusions: The results of this 54-month post-operation tracking observation revealed a rapid decrease in Trx1 levels in the blood after surgery, which remained consistently downregulated without a statistical association with pathological findings. This suggests that Trx1 is related to the presence of tumor masses rather than the pathological characteristics of the tumor. It is likely that if any treatment causes the removal and suppression of BC, the level of Trx1 is kept low. Besides its already reported ability to detect BC in blood, Trx1 levels have the potential to serve as a monitoring biomarker in the management of BC patients after treatment.
Correlating survival outcomes in patients with advanced prostate cancer with novel hyperpolarized 13C MRI metabolic imaging biomarkers.
Authors: Chen Hsin-Yu , de Kouchkovsky Ivan , Bok Robert A. , Ohliger Michael A. , Wang Zhen J. , Gebrezgiabhier Daniel , Nickles Tanner , Carvajal Lucas E. , Gordon Jeremy W. , Larson Peder E.Z. , Kurhanewicz John , Aggarwal Rahul Raj , Vigneron Daniel B.
Published: June 2024

e15059

Background: Hyperpolarized 13C (HP 13C) MRI is a novel molecular imaging approach that detects aberrant aerobic metabolism, namely elevated rates of pyruvate-to-lactate conversion (kPL), in patients with advanced malignancies. Higher kPL has been shown to correlate with higher tumor grade among patients with localized prostate cancer (PC). This research sought to evaluate the correlation between kPL and clinical outcome measures in patients with advanced PC. Methods: Patients with metastatic or locally advanced PC (castration sensitive or resistant) were prospectively enrolled at our institution and underwent HP 13C MRI of one or more target lesions identified on prior conventional imaging. Voxelwise kPL values were computed in MATLAB using an inputless two site exchange model. kPL,median was defined as the median kPL value per-patient across all target lesions; kPL,kurtosis measured the tailedness of the kPL distribution per-patient. We retrospectively analyzed progression free survival (PFS) and overall survival (OS) in subgroups divided by metabolic activity below versus above cut-point (kPL,median <0.017 s-1 and ≥ 0.017s-1, respectively). Survival statistics were calculated using the Cox PH model. Results: Sixteen patients (6 with castration-sensitive and 10 with castration-resistant PC) were accrued. With a median follow-up of 22.0 months from the date of MRI, the lower-kPL subgroup had significantly longer median PFS (11.2 vs 0.5 months; p<0.01) and OS (NR vs 18.4 months; p<0.05) compared to the higher-kPL subgroup. By comparison, baseline serum PSA (PFS: p=0.19, OS: p=0.41) and LDH (PFS: p=0.60, OS: p=0.34) did not demonstrate a significant association with clinical outcomes. There was a strong negative correlation between kPL,kurtosis and OS (r = -0.75), and moderate negative correlations between kPL,median and OS (r = -0.45) as well as kPL,max with both PFS (r = -0.48) and OS (r = -0.54). There was no significant kPL,median difference between castration-sensitive and resistant subgroups (0.015±0.011 vs 0.016±0.006 s-1, p>0.8). Conclusions: HP 13C MRI-derived non-invasive metabolic biomarker kPL,median significantly correlated with clinical outcome measures in a retrospective analysis of patients with advanced PC, outperforming established serological prognostic markers PSA and LDH. Limitations include our small sample size, retrospective design, and heterogeneous patient population. Nevertheless, these encouraging preliminary results support further investigation of HP 13C MRI as a prognostic and/or predictive PC biomarker in multi-center prospective imaging trials. [Table: see text]
Development of custom amplicon-based test systems for detecting KRAS, NRAS, and BRAF gene mutations in colorectal cancer using next-generation sequencing (NGS).
Authors: Zhusina Julia , Aksenova Elena , Larionova Kristina , Nikolaeva Anastasiia , Sluchanko Olesya , Vvedensky Andrey , Bazhenova Julia , Pyankov Denis , Korostelev Sergey
Published: June 2024

e15061

Background: Polymerase chain reaction (PCR)-based mutation diagnostics in colorectal cancer is widely available. However, PCR has limitations in identifying rare mutations and precise mutation coordinates. Targeted sequencing, though promising, often incurs high costs and longer research durations, demanding higher DNA sample quality. Our study demonstrates the benefits of using a customized amplicon test system for diagnosing somatic mutations in tumor tissue, including detecting rare mutations not captured by PCR, requiring less input biomaterial, and similar research costs. Methods: A targeted NGS assay system was developed using region-specific primers for KRAS (exons 2, 3, and 4), NRAS (exons 2, 3, and 4), and BRAF (exon 15). Library preparation involved a three-step PCR process: Target PCR incorporating Illumina overhang adapter sequences, Index PCR introducing multiplexing indices and sequencing adapters, and PCR cleanup using magnetic beads. Sequencing utilized MiSeq v2 reagents with paired 300‐bp reads, generating high-quality, full-length reads. Validation included re-testing known samples. Tumor cell percentages in FFPE specimens were determined, and DNA was extracted using the QIAamp DNA FFPE Tissue Kit. Data analysis utilized proprietary software. Results: Out of 1234 samples, 1133 were tested, with mutations detected in 685 samples (60.45%). KRAS mutations were found in 548 (48.36%), NRAS mutations in 40 (3.5%), and BRAF mutations in 88 (7.7%) samples. Double mutations were observed in 9 samples (0.79%). Data on rare and double mutations are presented in the table. Conclusions: The developed test system accurately identifies essential mutations in colorectal cancer, including rare and potentially clinically significant variants. The required DNA amount ranged from 10 to 30 ng in 5 μl, nearly ten times less than well-known commercial PCR test systems like COBAS (Roche) and therascreen (QIAGEN). The cost of the study is comparable to PCR with a minimum study duration of 4 days. [Table: see text]
Next-generation sequencing in patients with lung cancer undergoing immunotherapy: Retrospective analysis.
Authors: Batra Akshee , Khosla Atulya Aman , Alejos David , Kim Jinah , Searles Sienna , Chitkara Akshit , Jatwani Karan , Vyas Abhinav , Rehman Hibba tul , Ahmed Shahid Sattar , Singh Rohit
Published: June 2024

e15071

Background: Identifying targetable oncogenic drivers and resistance mechanisms by Next-generation sequencing (NGS) is critical in Non-Small Cell Lung Cancer (NSCLC). Methods: We conducted a retrospective study at the University of Vermont Center to assess the utilization of NGS in NSCLC. We examined the medical records of NSCLC patients who received Immune Checkpoint Inhibitors (ICIs) as a first-line therapy between January 2017 and June 2022. We collected demographic data, including age, sex, ethnicity, cancer stage, NGS, mutations and survival data. Survival analysis was performed for the most common mutation by measuring the Hazard Ratio (HR) via Cox regression of different mutations compared to the whole cohort. Results: We identified 95 NSCLC patients with 52.6% males, 94.7% whites and a mean age of 63.4 years (Standard Deviation (SD): 11.34). 67.4 % received Pembrolizumab and 30.5% got Durvalumab. Most patients had stage 4 and stage 3 cancers, with 54.7% and 35.8%, respectively. Mean ECOG of 0.9 (SD: 0.7), 34% had average body mass index, and overall mortality was 41%. PD L1 expression and NGS were reported in 81% of cases. NGS was reported in 88.5% of stage 4 and 76.5% of stage 3 categories. 41.8% had a type of KRAS mutation, with KRAS p.G12C being the most common. 24.1% of cases had no mutation. The mean survival months ranged from 7.6 months in MET to 52.4 months in RET mutation. Survival analysis showed decreased mortality in EGFR mutation, as seen in Table. Conclusions: The rate of NGS testing at our rural academic center in Vermont is on the higher side of the national average NGS testing, but the turnaround time (TAT) of 28 days is suboptimal compared to NCI centers. Strategies to reduce TAT need to be implemented to get timely essential for tailoring therapies in patients with NSCLC. Further research is needed to explore the prognostic utility of mutations in NSCLC patients undergoing ICIs. [Table: see text]
Characterizing clinical trials for CAR T targeting solid tumors from 2018 to 2023: A systematic review.
Authors: Wesson William , Ayoobkhan Fathima Shehnaz , Mahmoudjafari Zahra , Mushtaq Muhammad Umair , Abdallah Al-Ola A. , Sun Weijing , Anwer Faiz , Doolittle Gary C. , McGuirk Joseph , Al-Rajabi Raed Moh'd Taiseer , Baranda Joaquina Celebre , Ahmed Nausheen
Published: June 2024

e15080

Background: In the last decade, there have been many advances in the treatment of solid tumors, including new chemotherapy agents, immunotherapy, and most recently, cellular therapies. Chimeric antigen receptor T-cell (CAR T) therapy, first approved for acute lymphoblastic leukemia in 2017, represented a paradigm shift in hematologic malignancies, producing response rates that dramatically outpaced alternative regimens in a relapsed/refractory patient setting. Approvals in large B-cell lymphomas and multiple myeloma followed. Excited by the potential of CAR T, investigators worldwide have initiated trials to investigate the use of CAR T in solid tumors. This review explores the trials conducted globally, evaluating the potential molecular targets and the status of current clinical trials. Methods: This systematic review identified CAR T clinical trials specifically targeting solid tumors starting in 2018 to 2023 registered at ClinicalTrials.gov as of January 8, 2024. Trial-related variables including trial phase, primary trial site location, primary endpoints, start and end dates, and molecular target were captured. Results: We screened 110 clinical trials, ultimately including 103 studies for analysis after excluding trials without a CAR T construct in the methods. The number of new clinical trials increased over time, with a significantly larger increase (440%) seen with non-US sponsors compared to US sponsors (100%), p< 0.0001. Only 19 trials (18%) are/were being conducted in the United States in the studied time period. There were 33 unique molecular targets used, with mesothelin (17%), and the claudin protein family (13%) as the most frequented targets. Conclusions: The success that CAR T has demonstrated in hematologic malignancies has created great hope in solid tumor malignancies, although tempered by differences between the two categories. Unlike hematologic cancers, solid tumors exhibit significant biomarker variation, with interpatient biomarker expression varying greatly, even within the same tissue diagnosis. To deal with this issue, the majority of clinical trials that were reviewed here were not restricted to a single disease location such as breast cancer or esophageal cancer but were rather restricted by the expression of the targeted epitope, to allow for the heterogeneity inherent in these tumors. As presented here, substantial efforts are being made worldwide to improve these technologies, but the United States appears to be lagging in clinical trial efforts, compared to other nations. Further investigation is warranted into this topic, as the usage of CAR T quickly spreads from a therapy only used in hematology to one with promise in solid tumors, infectious diseases, and beyond.
Pharmacodynamics of venetoclax plus cirtuvivint a first-in-class splice variant regulator.
Authors: Govindharajulu Jeevan P , Dougherty Kelly , Miner Tiffanie , Hollingshead Melinda G. , Gore Steven , Parchment Ralph E. , Doroshow James H. , Srivastava Apurva K.
Published: June 2024

e15093

Background: NSC835563 (SM08502, cirtuvivint) is a first-in-class pan CDC-like kinase (CLK) and dual specificity tyrosine kinase (DYRK) inhibitor that targets alternative splicing of genes in multiple pathways and modifies their protein expression. Preclinical screening of hematologic malignancy models has shown sensitivity to cirtuvivint, leading to proposed clinical trials in AML in combinations with venetoclax. We performed pharmacodynamic studies to identify probable mechanisms of combination activity in AML models. Methods: In vivo tolerability, efficacy and pharmacodynamic (PD) studies were performed in two AML xenograft models, MV411 and KG1a in NSG mice, at 6.25-25 mg/kg PO cirtuvivint and 25 mg/kg PO venetoclax. Body weights (BW) and tumor volumes were recorded periodically to assess toxicity and anti-tumor efficacy. Tumor tissue samples were collected at 6 and 24 h post venetoclax to assess PD response. Multiplexed analysis of apoptosis pathway proteins/protein-protein complexes was performed by clinically validated assays (PMID 26446940). Results: Cirtuvivint alone at high doses (25 mg/kg) caused tumor regressions in MV411 but only a modest tumor growth inhibition (TGI) in KG1a, a resistant AM model. Importantly, the lowest dose of 6.25 mg/kg cirtuvivint combined with 25 mg/kg venetoclax led to tumor regression in the MV411 model and a moderate TGI in KG1a. Cirtuvivint alone caused a transient 25% reduction (p<0.05) in Mcl-1 levels at 6 h post dose in MV411. The venetoclax combination triggered a sustained (for 24 h) 50-75% disruption of Bcl-2 and Mcl-1 complexes with Bax and Bim, resulting in >20-fold increased mitochondrial Bax/Bak heterodimer and >10-fold increased cytosolic cleaved caspase-3. In KG1a, combination treatment resulted in only modest (<20%) changes in biomarkers. Overall, biomarkers provided evidence of the combination MoA. Conclusions: Venetoclax and cirtuvivint in combination effectively induced tumor regressions at low tolerable doses in an AML model. Mitochondrial Bax/Bak heterodimer provided a sensitive biomarker of combination activity. Cirtuvivint contributed its combinatorial effect primarily through disruption of Bim complexes and inhibition of Mcl-1. PD biomarkers identified in this study can confirm MoA of drug combination in ongoing clinical trials.
First-in-human study of ZG0895, a TLR8 selective agonist, as monotherapy in patients with advanced solid tumors.
Authors: Sun Yan , Chai Xiaoli , Wang Zhen , Qu Song , Wu Lihua , Liu Linlin , Liu Yanyan , Zhu Ji
Published: June 2024

e15103

Background: ZG0895 is a potent and novel Toll-like receptor (TLR) agonist that shows a highly selective activation of TLR8. It inhibits tumor growth by launching TLR8 downstream signal cascades, thus activating both innate and adaptive immune systems. We report preliminary results from a phase I, first-in-human, dose escalation study evaluating the safety, pharmacokinetics (PK) and antitumor activity of ZG0895 in patients with advanced solid tumors. Methods: Eligible patients previously treated with or intolerant to available standard systemic therapy(ies), received subcutaneous (s.c.) injection of ZG0895 weekly. If tolerated during the first treatment cycle (21 days per cycle), patients would continue weekly s.c. administrations of ZG0895 until disease progression, loss of clinical benefit, or development of unacceptable toxicity. Dose escalation scheme for ZG0895 was planned with eight dose levels (0.06, 0.18, 0.37, 0.75, 1.50, 2.25, 3.00, 3.75 mg/m2) according to an accelerated titration in the first two dose levels and the standard “3+3” design in the rest dose levels. Primary end points are the safety, tolerability, and recommended phase 2 dose (RP2D) of ZG0895. Secondary endpoints include overall response rate (ORR), disease control rate (DCR) and progression free survival (PFS) per the Response Evaluation Criteria in Solid Tumors version 1.1, as well as pharmacokinetics. Results: At data cut-off (December 25, 2023), 7 patients (5 males and 2 females), with the median age of 59 (range: 38-74) years old, received weekly s.c. injections of ZG0895 at the dose levels from 0.06 mg/m2 to 0.75 mg/m2 and completed the DLT observation period. Of the 7 patients, 4 (57.1%) received at least 3 lines of prior antineoplastic therapies, and 3 (42.9%) had exposed to PD-(L)1 inhibitors previously. No dose limiting toxicity events were reported. Five patients (71.4%) experienced grade 1 or 2 treatment-related adverse event (TRAE), and the most frequent events were injection site pain, hypertriglyceridaemia and proteinuria. None of patients experienced ≥grade 3 TRAE. Two patients experienced SAEs (intestinal obstruction and tumour haemorrhage), and both events were not related to ZG0895. The Cmax and AUC increased from 0.06 to 0.18 mg/m2 approximately in dose proportion. Conclusions: During the first 4 dose groups, ZG0895 was well tolerated in patients with advanced solid tumors. Phase I dose escalation of ZG0895 are underway in higher doses. Clinical trial information: NCT05877664 .
Surufatinib plus PD-1/L1 inhibitors as maintenance therapy following first line (1L) platinum-based chemotherapy combined with PD-1/L1 inhibitors in patients (pts) with extensive-stage small cell lung cancer (ES-SCLC).
Authors: Hu Yi , Chen Jianhua , Lv Dongqing , Wang Jinliang , Ma Junxun , Yi Tienan , Wu Shikai , Zhou Xiangdong , Zhang Xingxing , Chen Dongmei , Fan Songhua , Shi Michael , Su Weiguo
Published: June 2024

e15109

Background: Pts with ES-SCLC have a poor prognosis. PD-1/L1 inhibitors combined with chemotherapy as 1L treatment has been demonstrated to improve the survival. Yet, pts are prone to progression after chemo-immunotherapy followed by anti-PD-1/L1 monotherapy. A multicenter, single-arm phase II study was conducted to evaluate the efficacy and safety of surufatinib (a small-molecule inhibitor of VEGFR 1-3, FGFR1 and CSF-1R) combined with PD-1/L1 inhibitors in pts with ES-SCLC as 1L maintenance therapy. Methods: Key inclusion criteria were cytologically or pathologically confirmed ES-SCLC, ECOG PS 0-1, no disease progression after 4-6 cycles platinum-based chemotherapy combined with PD-1/L1 inhibitors. Enrolled pts received surufatinib (250mg, po, QD) plus PD-1/L1 inhibitors (same as that in prior 1L therapy: Durvalumab, Sintilimab, Toripalimab or Serplulimab) until disease progression or intolerable toxicity. The primary endpoint is progression free survival (PFS) per RECIST 1.1 by investigator. Results: From Sept 2022 to July 2023, 21 pts were enrolled. The median age was 62 years. 90.5% were male, 85.7% were former and current smokers and 52.4% had ECOG PS of 0, 11 pts completed 6 cycles of platinum-based chemotherapy combined with PD-1/L1 inhibitors, and 12 pts received durvalumab in 1L therapy. As of 20 Nov, 2023, the median follow-up duration was 9.2 months. Objective response rate (ORR) was 14.3% and DCR (disease control rate) was 71.4%. The mPFS of 1L maintenance therapy was 4.0 months (95%CI: 2.0-5.6). The mPFS from 1L treatment to disease progression was 8.7 months. mOS was not reached, with 3 mo- , 6 mo- and 9 mo- OS rate was 100%, 94.4% and 75.6%, respectively. 21 (100%) pts experienced treatment-emergent adverse events (TEAEs), and 8 (38.1%) pts experienced grade ≥3 TEAEs, most commonly with platelet count decreased, neutrophil count decreased and pneumonia. There was no treatment-related death. Conclusions: Surufatinib combined with PD-1/L1 inhibitors showed encouraging efficacy and tolerable safety profile as 1L maintenance therapy. Further OS follow-up is warranted. Clinical trial information: NCT05509699 .
Examination of in vitro and in vivo antitumor activity of PARP1 selective inhibitor D0112-005.
Authors: Li Li
Published: June 2024

e15115

Background: The approved PARP inhibitors have demonstrated efficacy in ovarian, breast, prostate, and pancreatic cancers, particularly in homologous recombination repair (HRR)-deficient tumors, including BRCA mutant tumors. The severe hematological toxicity of first-generation PARPi in combination with chemotherapy is due to the lack of selectivity for PARP2. So, we developed selective PARP1 inhibitor D0112-005 with the aim to improve safety and efficacy. Methods: The selectivity of D0112-005 on PARP1, PARP2 was measured by chemiluminescent assay kit and PARP trap™ assay kit. The anti-proliferative ability of D0112-005 was evaluated by CCK-8 in BRCA mutant cell lines. In vivo anti-tumor effect of D0112-005 was evaluated in MDA-MB-436 BRCA1 mutant xenograft model. The potential for hematologic toxicity was evaluated in rats for 28 days repeat-dose and dogs for 14 days repeat-dose. Results: D0112-005 is a highly potent and selective inhibitor of PARP1 with 2000-fold selectivity for PARP1 over PARP2 and PARP3. D0112-005 trapped PARP1-DNA with an EC50 value of 6.49 nM. In contrast, the EC50 of PARP2-DNA trapping was 430μM. These data demonstrate that D0112-005 is a potent and selective PARP1 trapper. D0112-005 showed high anti-proliferation activity against BRCA mutant MDA-MB-436 and HCC1395 cell lines, with IC50 values of 2.06 nM and 2.446 nM, respectively. In the MDA-MB-436 BRCA1m xenograft model, a dose-dependent anti-tumor effect was observed after 21 days administration, with TGIs of 38.77%, 106.7% and 111.73% at the dose of 0.1, 0.3 or 1 mg/kg once daily by oral, respectively. In the 1 mg/kg group, the anti-tumor efficacy was maintained after 14 days of drug withdrawal. D0112-005 showed well tolerance without bodyweight loss. In rat 28 days repeat dose study, D0112-005 100mg/kg had less changes on hematologic parameters compared with Olaparib. The main toxic reaction of D0112-005 (10mg/kg) was reversible thrombocytopenia in dog 14 days repeated toxicity study. Conclusions: D0112-005 potently and selectively inhibits PARP1 resulting in excellent anti-tumor activity in vivo and in vitro, which also good safety profile in the repeated toxicity study in rats and dogs.
Safety and clinical efficacy of IOA-289, a novel autotaxin inhibitor, plus gemcitabine and nab-paclitaxel (GnP) in patients with previously untreated metastatic pancreatic ductal adenocarcinoma (mPDAC).
Authors: Melisi Davide , Quinzii Alberto , Valente Monica , Di Giacomo Anna Maria , Amato Giovanni , Simonetti Elena , Zecchetto Camilla , Casallino Simona , Leta Luigi , Messineo Luisa , Mendo Lucia , Hammett Tracey , Deken Marcel , Di Conza Giusy , Kaur Paramjit , Lahn Michael M. F. , Maio Michele
Published: June 2024

e15130

Background: Autotaxin (ATX) plays a critical role in inflammation and resistance mechanisms in a wide range of malignancies. IOA-289 is a novel inhibitor of ATX, with anti-fibrotic, immune-enhancing and anti-tumour activity. This first-in-human trial evaluated safety and tolerability, pharmacokinetic (PK)/pharmacodynamic (PD) profile of IOA-289 in combination with GnP. Methods: IOA-289 was investigated, in untreated mPDAC, in a dose escalation study evaluating the continuous twice daily dosing (BID). IOA-289 was initially administered for 7 days as a monotherapy (Cycle 0) before adding GnP at standard doses in 3 weekly schedule followed by 1 week pause (Cycle 1 onwards). Primary objective: Safety and tolerability. Secondary objectives: PK; PD (e.g., plasma LPA and serum CA19-9); radiographic responses (RECIST 1.1); PFS and OS. Results: Cohort 1 assessed the safety at 100 mg BID (n = 4), cohort 2 at 200 mg (n = 4), and cohort 3 at 400 mg (n = 5). Safety assessment shows no treatment-emergent adverse events led to study drug discontinuation, or a dose limiting toxicity. Most toxicities were consistent with the known toxicity profile of GnP. Median time on treatment for cohort 1 was 4.8 months, for cohort 2 and cohort 3 patients are still under treatment and clinical outcomes are not yet established but are projected to surpass the observation from cohort 1. Five patients are currently remain active on treatment No clinical responses were observed in cohort 1. In cohort 2, 2 out of 4 patients (50%) achieved a Partial Response (PR) at cycle 5 and 7 respectively, which was confirmed and durable. No mature data is available yet for later cohorts. Exposure to the compound resulted in reductions in multiple LPA species, with a protocol-defined inhibition of > 50% for over 24 hrs. Consistent reductions in levels of CA19-9 have been observed since cohort 2 (200 mg BID), with > 50% reduction already from cycle 2, with durable reductions lasting longer than 4 months. No mature data is available for later cohorts. Conclusions: IOA-289 is well tolerated at all dose levels in combination with standard GnP. Patients in the higher dose cohorts are experiencing robust CA19-9 reductions consistent with ORR. Occurrence of PRs occurred later than compared to historical controls and were durable, suggesting a differentiated mode of action. Clinical trial information: NCT05586516 .
Serabelisib, sapanisertib (PIKTOR) and paclitaxel: A combinatorial approach to improve PI3K/mTOR/AKT pathway inhibition and treatment response in solid tumors.
Authors: Starks David , Tyrakis Petros A , Steele Georgie , Kampjut Domen , Chirnomas Deborah , Williams Casey B. , Maddocks Oliver D. K.
Published: June 2024

e15134

Background: Despite high mutation rates in genes of the PI3K/mTOR/AKT pathway in cancer, therapeutic strategies to inhibit this pathway featuring single targeted therapies have achieved limited clinical success. An alternate approach inhibiting multiple parts of the pathway simultaneously demonstrated improved activity (Starks et al, GynOnc 2022). The Phase 1 study combined the targeted PI3K-alpha and mTOR inhibitors serabelisib and sapanisertib (PIKTOR) with paclitaxel showing reasonable safety and promising clinical efficacy in patients with advanced endometrial, breast and ovarian tumors that had progressed on prior taxane. The ORR was 47% including 3 complete responses, with a PFS of 11 months in 15 evaluable subjects (NCT03154294). We sought to better understand the mechanistic basis for the efficacy of this triplet drug combination in models of endometrial and breast cancer to support successful clinical development of this regimen. Methods: Signaling activity in PI3K/mTOR/AKT pathway was probed by western blot for phospho-S6 and phospho-4EBP1 in human endometrial and breast cancer cell lines with PI3K/mTOR/AKT mutations. Single and combinatorial dose-response curves were established for serabelisib, sapanisertib and paclitaxel versus FDA-approved pathway inhibitors. Mechanisms of cytotoxicity and paclitaxel sensitization were probed with cell death assays. The impact of single and combined agents on tumor growth was assessed with in vivo xenograft studies. Results: In human endometrial and breast cancer cell lines, the combination of serabelisib and sapanisertib achieved markedly improved PI3K/mTOR/AKT pathway inhibition versus FDA-approved single agents. Serabelisib and sapanisertib increased the cytotoxicity of paclitaxel, supporting prior work that identifies PI3K/mTOR/AKT pathway activation as a key mediator of taxane resistance. Further, interrogation of a range of clinically relevant doses and scheduling led to an optimized regimen in which serabelisib and sapanisertib substantially improved the response to paclitaxel in vivo. Conclusions: Simultaneous inhibition of PI3K-alpha, mTORC1 and mTORC2 with PIKTOR offers potential for superior PI3K/mTOR/AKT pathway inhibition, suggesting that rational drug combination approaches may offer two important benefits: (1) more complete PI3K/mTOR/AKT pathway inhibition by targeting multiple signaling nodes, and (2) greater tumor cell cytotoxicity by sensitization to taxanes. These data, combined with the promising efficacy and safety signal from PIKTOR plus paclitaxel in a Phase 1 trial (NCT03154294), provide a compelling rationale for further clinical investigation. Future studies will focus on tumors known to have high rates of PI3K mutations including gynecologic tumors where there is a high unmet need.
Prevalence of NTRK gene fusions in solid tumors in northeastern Mexico.
Authors: Cerda-Contreras Christopher , Oyervides Victor , Vidal-Gutiérrez Oscar , Noriega Maria Fernanda , Lozano Aguilar Mario
Published: June 2024

e15145

Background: Gene fusions (GF) are among the intricate hallmarks of cancer that lead to abnormal cell proliferation and survival. Neurotrophic tropomyosin receptor kinase (NTRK) gene fusions are frequent in rare solid tumors but less frequent in common ones. Scarce literature has evaluated the prevalence of this aberration estimated to be from 0.5 to 1% globally. For these particular type of tumors, multikinase inhibitors is an option aside from chemotherapy with good responses. Objective: To determine the prevalence of NTRK gene fusions in a Mexican population. Methods: Sociodemographic, clinical, and histopathological data were collected in a single center from databases of Pathology and Oncology Departments of Hospital Universitario Dr. José E. González in Northeastern Mexico. Patients of all ages with solid tumors were included if tested positive for Pan-TRK by immunohistochemistry (IHC). Confirmation for gene fusion was made using Next Generation Sequencing (NGS) technology in formalin-fixed paraffin-embedded tissue. Results: A total of 156 patients from 2021 to 2023 were included for analysis. 67 (42.9%) did test positive for IHC. Of these, 52.2% were male and 20.8% were pediatric. Adult and pediatric median age of 57 and 13 years, respectively. Most frequent tumors locations were central nervous system & extremities. Gene fusion anomaly was confirmed in 6 patients. Among these, 83.3% were male and 16.7% pediatric population. Only NTRK1 and NTRK3 were found in gene fusions. Four translocations were prevalent TPM3:NTRK1 and ETV6:NTRK3 with 2 cases (33.3%), respectively. Followed by LMNA:NTRK1 and EML4:NTRK3 each with one patient. For location, arranged in descending order, head and neck (33.3%), extremities (33.3%), central nervous system and occult primary tumors both 16.6%. The only non-adult tumor reported was infantile fibrosarcoma. Prevalence was estimated to be 3.8% in our population. Conclusions: Understanding the molecular biology of tumor cells enables the development of targeted treatments other than chemotherapy. In our population, NTRK gene fusions were a little more prevalent (~4%) than global estimation. Unfortunately, in Mexico there's a lack of access to multikinase inhibitors. Further studies with large samples are required in Mexico and all over the world to afford access to these tumor-agnostic therapies.
CK2 expression in cancer and associated clinical characteristics.
Authors: Wilson Nicholas , Kreber Isabelle , Figueroa Cristián , Dominguez Isabel M. ,   Dominguez Lab Group
Published: June 2024

e15156

Background: The protein casein kinase 2 (CK2) is a ubiquitously expressed, highly pleiotropic kinase. CK2 may have incredibly varied substrate specificity and catalytic activity, as it functions as both a tetrameric and monomeric enzyme. CK2 participates in many cellular processes such as cellular proliferation, growth, and survival, and has significant potential to assist in oncogenic signaling. We and others have demonstrated CK2 gene and protein overexpression, and sometimes underexpression, in a variety of cancers. Here we investigate how the expression of CK2 subunits in cancer is associated with clinical characteristics in several distinct cancer types. Methods: Data analysis was performed on 32 non-overlapping cancer datasets obtained from The Cancer Genome Atlas (TCGA) and Broad GDAC Firehose Legacy projects, one dataset from Cancer Cell Line Encyclopedia (CCLE), and normal tissue datasets from Gene Expression Omnibus. Statistical analysis was performed using RStudio to explore the relationship between the expression levels of the three CK2 alpha transcripts (CSNK2A1, CSNK2A2, and CSNK2A3) and beta transcripts (CSNK2B) with sample clinical characteristics provided by TCGA/Broad. Relationships between CK2 expression and cancer-type specific characteristics were also explored, such as KRAS mutations in colorectal adenocarcinoma and serum AFP at sample procurement in hepatocellular carcinoma. CCLE data was used to explore correlations between cancer-type dependent CK2 gene expression and half maximal inhibitory concentration (IC50) of over 250 anticancer drugs. Tumor Immune Estimation Resource (TIMER) 2.0 was used to assess the relationship between CK2 subunit expression and tumor immune infiltration. Results: As seen in our previous analysis, CK2 transcripts were upregulated in the majority of cancer types analyzed. We also found that CK2 transcript upregulation correlated with worse survival outcomes in several previously unstudied cancers. CK2 expression differed significantly between cancer subtypes such as in ductal carcinoma and lobular carcinoma in breast cancer. CK2 expression significantly correlated with tumor grade, TNM staging, clinical staging in certain cancer types. CK2 expression significantly correlated with altered response to various anticancer drugs in certain cancers. CK2 expression was associated with both increased and decreased immune infiltration in a variety of cancers. Conclusions: Overall, this study demonstrates that CK2 transcript expression correlates with a variety of cancer-type dependent characteristics and clinical outcomes. As a result, CK2 may be useful as a prognostic biomarker and therapeutic target.
Gene fusions: A retrospective analysis of therapies and treatments of MTB patients over 7 years.
Authors: Randall Jamie , Swain Whitney Rose , Chouraichi Safae , Wang Hongkun , Winer Arthur , Huynh Jasmine , Wadlow Raymond Couric , Cannon Timothy Lewis
Published: June 2024

e15183

Background: Gene fusions (GF) are less common than single nucleotide variants, amplifications, and deletions, but have been suggested to be more predictive of responses to specific molecularly targeted therapies than other types of molecular alterations. We reviewed our institutional trends for overall survival in our molecular tumor board database based on the receipt of molecularly targeted therapy. Methods: We identified patients with non-hematologic malignancies and gene fusions (GF) identified by DNA based next generation sequencing (NGS) and reviewed by the Inova Schar Cancer Institute Molecular Tumor Board (ISCI MTB) between March 1, 2016 and March 1, 2023. GFs were confirmed by re-evaluation of next generation sequencing, and we determined the number of patients who received molecularly targeted therapy (RTT) specific for the GF. We evaluated overall survival (OS) in the RTT cohort and in the cohort that did not receive targeted therapy (NTT). TMPRSS fusions in prostate cancer were excluded from this analysis. Results: There were 93 patients with gene fusions in advanced staged cancers that met study criteria. Twenty-three were lost to follow up, transferred care outside ISCI, or enrolled in hospice. Of 70 stage IV patients reviewed, thirty-seven were found to have received GF targeted therapy. OS for all patients was 28.5 months. Patients in the RTT cohort had a median OS of 45 months and patients in the NTT cohort had an OS of 26.8 months (p-value = 0.16, Log-rank test). Conclusions: Targeted therapy in solid tumors with gene fusions is associated with prolonged overall survival. It is critical for MTBs to use NGS platforms that identify GF. Further studies examining OS and GF are warranted. [Table: see text]
A phase Ib study of JMT103, a receptor activator of NF-kB ligand (RANKL) antibody, in patients (pts) with bone metastases from solid tumors.
Authors: Ran Ran , Li Hongtao , Zhou Huan , Sun Tao , Zang Ai-min , Hongqian Guo , Xie Hua , Wu Shikai , Yan Yong , Yin Xing , Xiong Hailin , Li Hong , Yuan Jing , Li Huiping , Li Jin
Published: June 2024

e15190

Background: JMT103 is a human IgG4 monoclonal antibody against RANKL and blocks the RANK signaling in osteoclasts, thus suppressing bone resorption. This phase Ib study aims to demonstrate the activity of JMT103 in bone metastases patients with solid tumors. Methods: In this randomized, multi-center, open-label, phase Ib study, adult pts with bone metastases from solid tumors were enrolled and randomized at a 1:1:1 ratio to receive JMT103 subcutaneously at 120mg every 4 weeks (Q4W, Cohort 1), 120mg every 8 weeks (Q8W, Cohort 2) and 180mg Q8W (Cohort 3) up to 49 weeks. The primary endpoint was the percent change from baseline to week 13 in creatinine-adjusted urinary N-telopeptide (uNTx/Cr). Secondary endpoints included safety, anti-drug antibodies (ADA) positivity, the percentage of patients who experienced on-study skeletal-related events (SREs), and ≥ 2-point decreases in pain with Brief Pain Inventory – Short Form. Results: At database lock (Mar. 31, 2023), 295 pts were enrolled; 293 were treated with JMT103 and eligible for efficacy and safety evaluation (96 pts in Cohort 1, 97 pts in Cohort 2, and 100 pts in Cohort 3). The median age was 58 years (Interquartile range [IQR] 51, 66), and the primary tumor types were mainly breast (145, 50%) and prostate cancer (44, 15%). At week 13, the median (IQR) percent change in uNTx/Cr was - 80% (- 93%, - 50%) in Cohort 1, - 73% (- 94%, - 34%) in Cohort 2, and - 76% (- 92%, - 40%) in Cohort 3, respectively. The incidence of SREs in the three cohorts was 3%, 6%, and 7%, respectively. Among the 33 pts in Cohort 1, 35 pts in Cohort 2, and 37 pts in Cohort 3 with baseline pain scores ≥ 2, 61% in Cohort 1, 46% in Cohort 2, and 54% in Cohort 3 experienced ≥ 2-point decreases in pain at the first post-treatment visit (Day 15). For ADA analysis, only 1 (1%) pt in Cohort 2 with a negative result at baseline tested positive after treatment. The table shows the overall summary of the safety profile. Most of TRAEs were low in grade and resolved quickly. The most common TRAEs (any grade) were hypocalcemia (68, 23%), hypophosphatemia (67, 23%), and increased aspartate transaminase (35, 12%). Among the 40 cases of grade-5 TEAE, only 1 was reported as a TRAE (pneumonia); the rest were unrelated to JMT103. Conclusions: Our study demonstrated a promising efficacy of JMT103 in reducing bone metabolism biomarker and a good safety profile with low immunogenicity. Clinical trial information: NCT04630522 . [Table: see text]
Single-center retrospective analysis of second-line treatment with regorafenib in patients with advanced colorectal cancer among the COVID-19 pandemic.
Authors: Xiao Yu , Liu Zhentao , Cao Baoshan
Published: June 2024

e15552

Background: Regorafenib targets multiple tyrosine kinases that has been approved for the third-line treatment in metastatic colorectal cancer (mCRC) patients in China. Here, We retrospectively analyzed the efficacy and safety of regorafenib alone or combined with chemotherapy/immunotherapy in the second-line treatment for those who cannot visit hospital for their chemotherapies because of the COVID-19 pandemic. Methods: Individual patient data from Peking University Third Hospital were analyzed retrospectively from January 2020 to September 2023. The primary endpoint was progression-free survival (PFS), and secondary endpoints were overall survival (OS) and safety. Results: The median age of 31 patients was 65 years, the median PFS was 6 months (1–21 months), and the median OS was 20 months (3–38 months). PFS tended to be prolonged with regorafenib plus capecitabine or immunotherapy in 12 subjects versus regorafenib alone in 19 subjects (8 months vs. 4 months, P = 0.306), with no statistical difference, and so did OS (27 months vs. 15 months, P = 0.899).The analysis of PFS (2.5 months vs. 7 months vs. 4 months, P = 0.164) and OS (13 months vs. 28 months vs. 20 months, p = 0.417) in patients with liver, lung, or abdominal/peritoneal metastases at the initiation of treatment demonstrated poor survival prognosis in patients with liver metastasis. Multivariate analysis showed that regorafenib combined with capecitabine or immunotherapy (wald = 5.766, p = 0.016) and non-liver metastasis (wald = 4.223, p = 0.040) were independent prognostic factors for PFS in the second-line treatment. Adverse drug reactions (ADRs) mainly included hand-foot skin reactions (HFSRs), fatigue, hypertension, and proteinuria, due to which 3 subjects discontinued the treatment. The incidence of Grade 3/4 ADRs was 19.3%, 16.9%, 12.9%, and 9.6%, respectively. Conclusions: Regorafenib alone or combined with chemotherapy/immunotherapy is safe and feasible in the second-line treatment for advanced colorectal cancer, and therefore further prospective studies can be conducted to explore combination therapies.
Impact of DNA damage repair alterations on real-world response to therapy in metastatic colorectal cancer.
Authors: Miotke Laura , Norton Carter , Nevala-Plagemann Christopher Duane , Florou Vaia , Rubnitz Zach , Garrido-Laguna Ignacio
Published: June 2024

e15557

Background: Alterations in the DNA damage repair (DDR) pathway genes contribute to tumor development. These alterations can be exploited by cytotoxic chemotherapy regimens that induce DNA damage. Platinum chemotherapy agents have been shown to be particularly effective in breast and ovarian cancer patients with alterations in the DDR pathway. However, the clinical impact of DDR alterations in metastatic colorectal cancer (mCRC) is still poorly understood. In this study, we utilize a large national database to evaluate clinical outcomes in patients with mCRC and alterations in DDR pathway genes. Methods: We reviewed 5602 patients that received standard fluorouracil based first-line chemotherapy regimens for mCRC using the nationwide Flatiron Health EHR-derived de-identified database. Chemotherapy regimens were categorized as a platinum-based doublet (FOLFOX, CAPOX), irinotecan-based doublets (FOLFIRI), or triplet (FOLFOXIRI). Overall survival (OS) was summarized within groups via Kaplan-Meier survival estimates. OS was compared between groups in the context of univariable and multivariable Cox proportional hazards models controlling for age, gender, DDR status, stage at diagnosis, ECOG, RAS/RAF status, MMR status, albumin and CEA at diagnosis. OS was defined as the time in months between date of first line therapy initiation to death. Results: DDR gene alterations were indentified in 35.7% (2001) patients.The most frequent mutations were in ATM (13.3%) and BRCA2 (8.3%). There was no significant difference in OS based on DDR mutation status. Within DDR altered patients, there was no difference in OS between those who received a platinum-based doublet, irinotecan-based doublet or triplet first-line therapy. Time to next treatment or death (TTNTD) was significantly improved with an irinotecan-containing doublet regimen and triplet regimen compared to a platinum-based doublet in a multivariable model (HR 0.79, p = 0.001 and HR 0.68, p = 0.002, respectively). There was no difference in OS in DDR-mutated patients that received an irinotecan-based regimen in the first line followed by an oxaliplatin-based regimen in the second line or the reverse sequence. When evaluating the impact of commonly co-mutated genes on survival we observed a worse OS in patients with a KRAS mutation in addition to a DDR mutation (HR 1.19, p = 0.045). An APC mutation was associated with an improved OS in the entire cohort, regardless of DDR status (HR 0.76, p < 0.001). Conclusions: In this real-world population, approximately one third of patients with mCRC harbored an alteration in a DDR pathway gene. In these patients, TTNTD was greater with irinotecan-containing first line therapies (doublet or triplet). However, OS was similar regardless of which first-line chemotherapy was used.