bluuebunny/crossref_metadata_2025 huggingface dataset:
Combination olaparib and durvalumab for patients with recurrent IDH-mutated gliomas.
Authors: Ramos Ronald , Climans Seth Andrew , Adile Ashley , Ghiassi Pegah , Baker Stephanie , Phillips Madeline J. , Zadeh Gelareh , Chen Eric Xueyu , Mason Warren P.
Published: June 2021

e14026

Background: Isocitrate dehydrogenase (IDH) mutations are frequently observed in low grade gliomas and secondary glioblastoma. Mutant IDH enzymes aberrantly convert α-ketoglutarate (αKG) to 2-hydroxyglutarate (2HG). Accumulation of 2HG inhibits αKG-dependent dioxygenases, many of which are involved in epigenetic regulation. This can lead to cellular dedifferentiation and tumor formation. IDH-mutated cancer cells exhibit defective homologous recombination repair, providing the rationale for investigating poly (adenosine 5’-diphophate-ribose) polymerase (PARP) inhibitors in these tumors. Blockade of programmed cell death ligand 1 (PD‐L1) re‐sensitizes PARP inhibitor treated cancer cells to T‐cell killing. We report the preliminary results of the glioma arm of a clinical trial of a PARP inhibitor, olaparib plus PD-L1 inhibitor, durvalumab, for IDH-mutated solid cancer. Methods: This is a single arm phase II basket study (NCT03991832). Patients with IDH-mutated solid tumors are divided into three cohorts; A: glioma; B: cholangiocarcinoma; C: all other solid tumors. Major eligibility criteria include IDH mutation by immunohistochemistry or sequencing, progressive disease with maximum two prior systemic therapies, Eastern Cooperative Oncology Group performance status (ECOG) 0 –1 and adequate organ function. Patients were excluded if they had received prior PARP inhibitors or anti-PD-1/PD-L1 antibodies. Patients were treated with olaparib 300 mg orally twice daily continuously and durvalumab 1500 mg IV every 4 weeks. Each cycle was 4 weeks. Tumor response was evaluated by MRI after every 2 cycles of study treatments using response evaluation criteria in solid tumors (RECIST). Results: As of Jan 2021, 9 patients were enrolled in Arm A, 7 men and 2 women. The median age was 42 years. Eight patients had IDH1 mutations and 1 had an IDH2 mutation. There were two patients with 1p/19q codeletion. Two patients had grade 2 tumors, four had grade 3, and three had grade 4 tumors. Median time since tumor diagnosis was 7 years. Objective response was seen in 1 patient with an IDH-mutated glioblastoma who remains on study treatments after 8 cycles. Six patients (67%) had tumor progression after two cycles. Two patients had stable disease as per RECIST but had clinical deterioration and did not continue the combined treatment. Common treatment emergent adverse events were all grade 1: fatigue (8 patients), nausea (6), abdominal pain (3), anemia (3), thrombocytopenia (3), and diarrhea (2). Median progression free survival was 2.5 months (range 1.9–8 months). Updated analysis and correlative studies will be presented at the meeting. Conclusions: Combination treatment with olaparib and durvalumab for patients with IDH-mutated glioma is well tolerated but appears to lack adequate antitumor activity. Clinical trial information: NCT03991832.
Clinical outcomes in patients with malignant brain tumors admitted to the ICU.
Authors: Maus Sarah , Lesser Glenn Jay , Bundy Richa , Hsu Fang-Chi , Miller Peter John
Published: June 2021

e14034

Background: Primary brain malignancy is distinct from other oncologic diagnoses in its presentation and course. Recent treatment advances have modestly improved survival; yet, prognoses for afflicted patients remain grim, which often leads to non-oncology providers questioning the pertinence of aggressive critical care in this population. By relating patient and disease factors with mortality rates in malignant brain tumor (MBT) patients admitted for critical care, we seek to identify valuable prognostic factors and clarify the expected outcomes following intensive care unit (ICU) admission among these patients. Methods: A single-institution retrospective review was performed of 80 primary MBT patients admitted to neuro- or medical ICUs over a five-year period. The Electronic Health Record (EHR) was queried to identify MBT patients who had been admitted to the ICU. Patients undergoing planned surgical resection or with post-operative complications were excluded, as were patients with brain metastases. A matched control group of 80 solid tumor (ST) patients (excluding brain tumors) was included for comparison. Similar aged matched controls were randomly identified via EHR over the same time period to include non-brain, ST patients admitted to the ICU. Demographic, oncologic, and admission data were related to outcomes, which included complication rates (ICU mortality, six-month mortality) and change in Karnofsky Performance Status (KPS) score. Results: The average age was 55.9 (20-83) and 62.8 (27-89) years in the MBT and ST group, respectively (p = 0.10). ICU mortality was 15% and 21% (p = 0.411) and six-month mortality was 46% and 65% (p = 0.10) in the MBT and control groups, respectively. The most common reasons for ICU admission were seizures (36%) and septic shock (21%) among MBT patients, compared to hypoxic respiratory failure (43%) and septic shock (30%) among ST patients. The MBT group’s KPS score decreased by 23.6 ± 26.82 during their ICU admission, while the control group KPS decreased by 27.0 ± 28.3 (p = 0.87). Average length of ICU stay was 3.82 ± 4.4 days in the MBT group, compared to 2.95 ± 1.83 days in the control ST group (p = 0.29). Average length of hospital stay was 9.07 ± 9.0 days in the MBT group and 8.67 ± 7.76 days in the ST group (p = 0.92). Conclusions: No significant difference was observed in ICU or 6-month mortality when comparing primary MBT and ST patients. Change in KPS score across ICU admissions was similar among the two groups. Our data indicate that despite their guarded prognosis, MBT patients fare no worse than those with other solid tumor types at our institution in the critical care setting. These similarities in mortality and functional scores justify medical ICU admission in patients with primary brain malignancy, and should inform intensivist and oncologist admission patterns.
Single agent activity of ONC201 in non-midline H3 K27M-mutant diffuse gliomas.
Authors: Odia Yazmin , Sumrall Ashley Love , Cloughesy Timothy Francis , Nghiemphu Phioanh Leia Leia , Hall Matthew David , Daghistani Doured , Mehta Minesh P. , Lassman Andrew B. , Arrillaga-Romany Isabel , Gardner Sharon L. , Tarapore Rohinton , Lu Guangrong , Allen Joshua E. , Wen Patrick Y.
Published: June 2021

e14037

Background: H3 K27M-mutant diffuse midline glioma is an invariably lethal form of brain cancer that disproportionately affects children and young adults and has no effective treatment following front-line radiation. The initial disease definition in the 2016 WHO Classification of Tumors of the Central Nervous System regarded the H3 K27M mutation as pathognomonic, though the definition was updated in 2018 restricting the diagnosis to histologically diffuse gliomas that involve midline CNS structures (cIMPACT-NOW update 2). ONC201 is an investigational anti-cancer small molecule, DRD2 antagonist and ClpP agonist that has induced durable tumor regressions by RANO-HGG criteria in a registration cohort of recurrent diffuse midline glioma, H3 K27M-mutant patients treated with single agent ONC201. Methods: We present 7 patients with H3 K27M-mutant diffuse gliomas were enrolled in ONC201 clinical studies, though excluded from the registration cohort due to involvement of non-midline CNS structures, all within the cerebral hemispheres (3 frontal, 1 temporal, 1 frontotemporal, 1 parietal, and 1 corona radiata). Results: Two of the 7 patients underwent objective responses by RANO-HGG criteria as assessed by investigator, which was associated with clinical benefit that included increased mobility and level of alertness. Conclusions: These results demonstrate that H3 K27M-mutant diffuse gliomas occur outside of midline CNS structures, and suggest that ONC201 has single agent activity in H3 K27M-mutant gliomas irrespective of CNS location.
Identification of a predictive biomarker and two pharmacodynamic biomarkers to ADG106 treatment, a novel anti-CD137 agonist antibody, in phase I clinical trials.
Authors: Zhang Li
Published: June 2021

e14505

Background: ADG106 is a fully human agonistic anti-CD137 monoclonal IgG4 antibody that mediates anti-tumor activities via unique mechanisms of action. Here we provide safety and efficacy updates from our phase I trials and report the findings of a predictive biomarker and two pharmacodynamic biomarkers which correlate with patients’ clinical responses to ADG106 treatment and demonstrate target engagement, respectively. Methods: Formalin fixed and paraffin embedded (FFPE), blood and plasma specimens were collected from 92 patients enrolled in our phase I trials. We measured expression across a panel of protein biomarkers in FFPE specimens using three highly sensitive detection technologies: multiple immunohistochemical (IHC) staining of protein expression, the BD Multitest 6-color TBNK reagent for profiling immune cell subpopulations, and the MSD-ECL electrochemiluminescence assay for detection of soluble CD137. Objective tumor responses were determined using RECIST v1.1 for solid tumor patients and Lugano classification for lymphoma patients. Results: As of November 30, 2020, ADG106 has demonstrated a favorable safety profile and efficacy in the phase I clinical trials with a disease control rate of 56%. From a retrospective analysis of 28 pretreatment FFPE specimens, we identified a predictive biomarker that correlated with tumor shrinkage upon ADG106 treatment. We identified four biomarker positive specimens from two patients with lymphoma and two with solid tumors. Three out of four biomarker positive patients achieved greater than 30% tumor shrinkage after 3mg/kg or 5mg/kg ADG106 treatment. One biomarker positive patient with stable disease received a low dose ADG106 treatment at 0.5mg/kg during dose escalation. None of the 24 biomarker negative patients showed significant clinical response. A tissue microarray study confirmed expression of this predictive biomarker in a variety of tumor types suggesting a broad indication for ADG106 therapy. Our biomarker studies also demonstrated target engagement with increased NK cell proliferation and soluble CD137 upon ADG106 treatment. Analysis of safety, efficacy, PK and PD data allowed us to select a recommended dose for the upcoming phase II study. Conclusions: We identified a biomarker predictive of response to antitumor CD137 blockade by ADG106, as well as demonstrated the involvement of NK cells in ADG106 mediated anti-tumor activities. In upcoming phase II trials, we plan to enrich for populations expressing this predictive biomarker to demonstrate a clinical benefit to ADG106 therapy further validating early biomarker-based patient stratification. We will also explore the potential of selecting patients for combination treatment with anti-PD-1 therapies. Clinical trial information: NCT03802955.
Gene expression profiling signatures for immunophenotyping of tumor microenvironment using HTG EdgeSeq Precision Immuno-Oncology Panel.
Authors: Jaramillo Melba C. , LaRoche Dominic , Ran Di , Navratil Marian
Published: June 2021

e14528

Background: Immunotherapy has revolutionized cancer treatment by harnessing the power of the patient’s immune system to fight the disease. While immunotherapies have become increasingly effective, the proportion of patients not responding to immunotherapy ranges between only 20-50%. New breakthroughs in the understanding of the tumor immune biology have led to the development of new, more effective therapies; however, these breakthroughs often hinge on tools that can elucidate the role and abundance of individual components of the patient’s immune system in the tumor microenvironment. Methods: This poster describes the performance of 26 gene enrichment signatures that allow for the measurement of the relative abundance of 23 individual immune and stromal cells in the tumor environment, in addition to providing composite inflammation, stroma and tumor microenvironment scores. These Research Use Only (RUO) signatures are based on gene expression profiling (GEP) data for 1,392 genes implicated in tumor-immune interaction generated using the HTG EdgeSeq Precision Immuno-Oncology Panel (RUO). The signatures were developed and validated using GEP data from 1,073 colorectal, gastric and ovarian cancer formalin-fixed paraffin-embedded (FFPE) tissue specimens. Results: The signature accuracy was independently verified by spiking known numbers of representative immune and stromal cells into an FFPE tissue lysate; the signature outputs were highly correlated to the number of immune and stromal cells present in the sample, with Pearson correlation coefficients ranging from 0.71 to 0.98. In addition, the outputs of some of the signatures were compared to multiple commonly used immunohistochemistry markers of immune cells in 61 non-small-cell lung carcinoma FFPE samples. The results showed a high degree of correlation, with Pearson correlation coefficients of 0.77 and 0.81 for CD4 and CD8, respectively. Conclusions: These immunophenotyping signatures provide a suite of robust tools for the characterization of the tumor microenvironment in order to better understand the tumor immune biology and mechanisms of resistance to immunotherapy. The signature scores can typically be generated from a single section of FFPE tissue using HTG’s extraction-free GEP technology and a fully automated bioinformatic pipeline available in the HTG EdgeSeq Reveal software.
Case series on the safety of mRNA COVID19 vaccines in cancer patients undergoing treatment.
Authors: Haroun Faysal , Alharbi Malak , Hong Alison
Published: June 2021

e14562

Background: Millions of vaccines have been administered since Emergency Use Authorization has been granted for two mRNA COVID-19 vaccines (mCV). The Center for Disease Control (CDC) and Prevention recommends that immunocompromised individuals with no contraindications to vaccines may receive an mCV. The CDC suggests that patients receiving cancer therapies should be consulted about the unknown vaccine safety profile and effectiveness. The American Society of Clinical Oncology recognizes that vaccine may reduce the risk of infection for individuals with cancer. Vaccine trials have not actively enrolled immunocompromised or patients on active cancer therapy; therefore, the potential side effects and efficacy of the mRNA vaccines in these individuals are unexplored. Per state guidelines, many patients with cancer undergoing treatment qualify for vaccination however current vaccine uptake in that population is unknown. Data in this specific high-risk population is needed to increase confidence in the vaccine. We explored adverse events (AE) to the mCV in a small cohort of patients undergoing cancer therapy. Methods: Our case series evaluated patients' tolerance to the voluntary but recommended 2 doses of the mCV while on chemotherapy (CX), checkpoint inhibitors (CPI) or tyrosine kinase inhibitors (TKI) at the George Washington University (GWU) Cancer Center in Washington DC. Patient chart review and phone interviews were conducted. Patients had independently signed up for the mCV at the GWU Hospital or through the DC Health Department. Patients were asked if they had experienced any of the commonly reported side effects listed by the CDC or others new symptoms receiving the vaccine. Results: 12 patients had voluntarily received the mCV, all patients were above the age of 65 with a mean age of 72 (66-85). ECOG performance status was 2 or above in 4 patients. 6 patients were receiving single agent CPI, 1 patient was on combination CX and CPI. 2 patients were on oral TKI for EGFR mutated lung cancer. 3 other patients were on combination CX with rituximab, ramucirumab or radiation. In the 2 patients on daily TKI, treatment was not interrupted for the mCV. In the 10 other patients, all but one patient received the mCV at least one week after the last therapy. Both mCV were tolerated without any life-threatening AE or hospitalization. Pain and swelling at the vaccine site were the most common local AE and reported in 7 patients. 6 patients reported systemic AE most commonly myalgia and headaches. Conclusions: This exploratory analysis in 12 patients with cancer undergoing treatment did not uncover any additional SE signals. Larger studies are needed to evaluate AE and efficacy and to guide recommendations for COVID19 vaccination in this patient population.
The incidence of occult endocrinopathies in patients with cancer undergoing immunotherapy in community practice.
Authors: Abdalla Ahmed , Singh Aditi , Gharib Hussein , Huber Benjamin , Malapati Sindhu Janarthanam , Hadid Tarik H. , Kafri Zyad
Published: June 2021

e14571

Background: Immune checkpoint blockade (IO) can induce inflammation of the pituitary, thyroid or adrenal glands. This usually results in non-specific symptoms such as headache, low-energy, nausea and vomiting, which can be difficult to differentiate from symptoms associated with cancer and therapy-related symptoms. Therefore, the exact incidence of endocrinopathies is exceedingly difficult to estimate in community practices. Also, the variable methods of assessment, diagnosis, and monitoring used in different clinical trials make it challenging to precisely measure the incidence of endocrinopathies. Methods: This is a single-center retrospective chart review of patients diagnosed with cancer receiving immunotherapy for cancer treatment who had routine hormone levels checked during their treatment. Data collected includes tumor types and the types of IO agents used. Laboratory data collected included thyroid-stimulating hormone (TSH), testosterone level, follicular stimulating hormone (FSH), luteinizing hormone (LH), cortisol levels. Results: In total, 75 patients were included in the study. The primary indication for IO was lung cancer in 43 patients (57%), genitourinary tumors (12%), melanoma (12%) and head & neck cancers (5.3%). Single-agent nivolumab (39 patients) was the most common IO agent used followed by single-agent pembrolizumab (22 patients), ipilimumab (11 patients), atezolizumab (3 patients), avelumab (1 patient) (There was one patient who got nivolumab initially and then pembrolizumab). Nine patients were treated with ipilimumab/nivolumab combination. The mean number of cycles received was 9.1. The total number of patients who developed at least one abnormal hormone level was 57(76%), with 33 out of 74 (45%) patients had at least one abnormal TSH, 29 out of 44 (66%) patients had at least one abnormal testosterone level, 10 out of 49 (20.4%) patients had at least one abnormal FSH and/or LH level, 36 out of 52 (69%) patients had at least one abnormal cortisol level. The mean number of days from starting IO to develop the first abnormal laboratory result was 106 days. Conclusions: The incidence of endocrinopathy was significantly high in patients receiving IO in this study, which is higher than what is reported in previous clinical trials. This could be due to frequent testing in asymptomatic patients and strict laboratory cut-off values which is not always clinically meaningful. This finding may highlight the importance of routine monitoring of the endocrine function during IO treatment. Routine measurement of hormone levels can detect asymptomatic endocrinopathy which may warrant further work-up and treatment. These findings should be validated in a larger prospective study.
Antitumor efficacy of 2-(6,8-dimethyl-5-nitro-4-chloroquinoline-2-yl)-5,6,7-trichloro-1,3-tropolone in lung cancer xenografts.
Authors: Lukbanova Ekaterina A. , Goncharova Anna S. , Volkova A. V. , Mindar M. V. , Zaikina Ekaterina V. , Khodakova D. V. , Shevchenko Alexey N. , Filatova Elena V. , Khomutenko Irina A. , Shvyrev Dmitry A. , Sayapin Yuriy A. , Gusakov Evgeniy A. , Lazutin Yuriy N.
Published: June 2021

e15008

Background: Lung cancer is the most common cancer worldwide. The efficacy of chemotherapy for this tumor does not exceed 40%. Moreover, all cytotoxic agents cause many side effects. The search for new substances with an antitumor effect seems to be relevant. Tropolone alkaloids, which are seven-membered non-benzenoid aromatic compounds, are promising inhibitors of tumor growth. The purpose of the study was to evaluate the antitumor efficacy of 2-(6,8-dimethyl-5-nitro-4-chloroquinoline-2-yl)-5,6,7-trichloro-1,3-tropolone in subcutaneous xenografts of lung cancer A549 cells in immunodeficient Balb/c Nude mice. Methods: The study was performed on a PDX model of lung cancer created by subcutaneous injection of A549 cell suspension, 5x106 cells in 0.2 ml of a solution of serum-free nutrient medium 199 and Matrigel (1:1). Animals were equally divided into 5 groups (each n = 5). Experimental groups 1, 2, 3 and 4 received 2-(6,8-dimethyl-5-nitro-4-chloroquinoline-2-yl)-5,6,7-trichloro-1,3-tropolone at doses of 0.0055, 0.055, 0.55 and 2.75 mg/g, respectively; the control group received 1% starch gel. The dynamics of the growth of a subcutaneous xenograft was evaluated by measuring tumor nodes. The volumes of tumor nodes were calculated using the Shrek’s formula for the ellipsoid: V = a×b×c×p/6, where V is the tumor volume (mm3), and a, b, c are the maximum dimensions of the ellipsoid in three planes (mm). The data were statistically analyzed using the Exel and Medstatistic progams. Results: The dynamics of subcutaneous xenograft growth in groups 1, 2, 3 and 4 significantly differed from the control group (p = 0.023). The average tumor volumes on the 39th day after the implantation in the control group and in experimental groups 1, 2, 3 and 4 were 1159.2, 895.3, 565.8, 80.7 and 76.7 mm3, respectively. The inhibition of tumor growth (ITG) was in direct proportion to the dose of the administered substance. Lower ITG(%) (32.4, 23.2 and 10.3% in experimental groups 2, 3 and 4, respectively) was associated with lower concentrations of О154 (0.55 mg/g, 0.055 mg/g and 0.0055 mg/g, respectively). Conclusions: The study demonstrated statistically significant differences in xenograft volume indices in all experimental groups compared to the control group.
Phase Ib/II study of capecitabine 7/7 schedule with neratinib in patients with HER2-positive metastatic breast cancer (MBC).
Authors: Wang Rui , Singh Jasmeet Chadha , Wong Serena Tsan-Lai , Lake Diana , Iyengar Neil M. , D'Andrea Gabriella , Brockway-Marchello Julia P. , Kaba Asta , Traina Tiffany A. , Robson Mark E. , Dang Chau T.
Published: June 2021

e15016

Background: Neratinib (N) is a potent irreversible inhibitor of HER1, HER2, and HER4. Capecitabine (X) at optimal dose of 7 days on and 7 days off schedule (7/7) is well-tolerated with low rates of ≥ grade (G3) diarrhea. Methods: We conducted phase Ib/II study of N with X (7/7) with loperamide and colestipol prophylaxis in patients (pts) with pretreated HER2+ MBC (NCT03377387). Eligible pts had normal left ventricular ejection fraction (≥ 50%), any and < 4 prior chemotherapy-based treatments in phase Ib and II, respectively. Primary endpoint of phase Ib is maximum tolerated dose (MTD) and phase II is response rate. Secondary endpoints are safety, tolerability, and progression-free survival. Exploratory endpoint is to quantify cell-free DNA (cfDNA), correlating with response. Phase Ib follows traditional 3+3 design with 4 dose levels. In phase II, if > 3/9 respond, study is expanded to 24. If > 10/24 respond, study is deemed successful. Results: As of 2-4-2021, 10 pts were enrolled in phase Ib. 4 pts were treated at dose level 1 (X at 1500 mg BID at 7/7 and N at 240 mg daily); 2/4 pts experienced with G3 diarrhea during cycle 1. Six pts were treated at dose level -1 (X at 1000 mg BID 7/7 and N at 240 mg daily); 1 (17%) developed G3 diarrhea. The MTD is X at 1000 mg BID 7/7 and N at 240 mg daily. Twenty-two of 24 pts have been enrolled in phase II. Of 22 pts, data show 6 with partial response, 8 with stable disease, 3 with progressive disease, and 5 have not been assessed radiographically. Overall, 6/22 (27.3%) and 1/22 (4.5%) had all G and G3 diarrhea, respectively. Other significant toxicities at MTD included G2 hand foot syndrome (n = 1, 4.5%), G1 fatigue (n = 1, 4.5%) and G1 nausea (n = 4, 18%). Conclusions: The MTD is X at 1000 mg BID at 7/7 and N at 240 mg daily. This combination is safe and well tolerated with G3 diarrhea rate of 4.5%, which is significantly lower than the X 14/7 schedule in NALA study. The phase II portion of the study is near completion and updated result will be presented. Analysis of cfDNA, to correlate with response for phase II portion, is ongoing. Clinical trial information: NCT03377387.
Anti-tumor activity of SKLB-0322, a novel EZH2 covalent inhibitor, in ovarian cancer.
Authors: Zhu Yongxia , Chen Xinyi , Zhang Qiangsheng , Shi Lihong , Yu Luoting , Xiao Hongtao
Published: June 2021

e15052

Background: Enhancer of Zeste Homolog 2 (EZH2) is the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2) that regulate downstream target genes expression, and then promotes tumor cell proliferation, metastasis and drug resistance. EZH2 also performs some functions in a PRC2-independent manner. Most of reported EZH2 inhibitors are S-adenosyle-methionine (SAM)-competitive inhibitor, and are less selective for EZH2 close homolog EZH1, which resulted in safety concerns and insufficient efficacy. To obtain irreversible EZH2 inhibitor, a novel covalent inhibitor was developed and characterized. Methods: SKLB-0322 and its derivatives were designed, synthesized and confirmed as EZH2 covalent inhibitor by us. The anti-tumor activities of SKLB-0322 were investigated by MTT assay, flow cytometry, and western blot assay. The reversible analog of SKLB-0322 (SKLB-0322’) was used as negative control. Results: SKLB-0322 inhibited EZH2 methyltransferase activity with nanomolar potency, while the inhibitory activities of SKLB-0322’ was reduced. The mass spectrometry (MS) analyses revealed that SKLB-0322 could efficiently forms a single modified covalent adduct. SKLB-0322 displayed noteworthy potency against ovarian cancer cell lines at low micromolar level and reduced the expression level of H3K27me3 in a concentration-dependent manner, which was about 5-fold more active than the reversible negative control SKLB-0322’. Besides, SKLB-0322 caused G2/M phase cell cycle arrest in A2780 and PA-1 cells. Furthermore, SKLB-0322 induced A2780 and PA-1 cell apoptosis in a time- and concentration- dependent manner. Conclusions: Our data clarified that SKLB-0322 is an EZH2 covalent inhibitor for ovarian cancer therapy which is worthy of further evaluation.
Inhibitory effect of lignans from Ailanthus altissima on proliferation of human lung cancer cells and its mechanism.
Authors: Wang Yu , Wang Siming , Wu Yibing , Dong Mei , Ni Zhiyu
Published: June 2021

e15059

Background: Plants are thought to contain compounds that inhibit the proliferation of cancer cells in vitro, and many attempts have been made to isolate anti-cancer drugs from plants. Ailanthus altissima is a family of Simaroubaceae, the bark is gray to grayish-black, because of the smell of the gland patches at the base of the leaves. 3,5,3-trimethoxy-8,1-neoligna-4,2,7,9,9-pentol (TNP) isolated from Ailanthus altissima. Methods: (1) Apoptosis was detected by flow cytometry: the cells were incubated with 10 mmol/L TNP for 24 h, and the cells were collected. The cell concentration was adjusted to 5×105 ̃ 5×106/ L. While propionate iodide was added for DNA fluorescence staining (Propidium Iodide, PI: 50 mg/L，triton-x100 1.0%). (2) The changes of p53, Bax and caspase-3 were detected by Western blot. The cells were cultured in 10 μmol/L cisplatin and TNP medium for 24 hours. Image J image analysis software is used for semi quantitative analysis. The data were expressed by mean standard deviation, and the mean values of each group were compared by analysis of variance and the least significant difference. There was a significant difference in P< 0.05. (3) A549 cells were treated with 10 μmol/L cisplatin and TNP. A549 cells were incubated with cisplatin and TNP, and then treated with solvent control (final concentration 0.1% dimethyl sulfoxide) with or without caspase inhibitor for 48 hours The OD value was determined by MTT method. Cell survival rate (%) = (OD value of control group /OD value of control group) 100%. Results: (1) The reverse effect of caspase inhibitor on the proliferation of A549 cells: the cell survival rates of A549 cells treated with 0.1, 1 and 10 μmol/L cisplatin and TNP were 96.11%, 72.36%, 27.57% and 71.42%, 28.97% and 4.34% respectively. The survival rate of A549 cells incubated with cisplatin and TNP 20 μmol/L increased to 100.00%, 81.92%, 57.54% and 85.69%, 48.57% and 16.95% respectively. Caspase inhibitor reversed the inhibitory effect of TNP on A549 cells. (2) The effect of TNP on apoptosis of A549 cells: after treatment with 10 μmol/L TNP for 24 h, the apoptosis rate of A549 cells was (24.01)%, which was significantly higher than that of the blank control group (6.79)% ( P< 0.05). (3) The results showed that the up regulation of p53, Bax and caspase-3 protein by TNP was 10 μmol/L. Conclusions: TNP can induce apoptosis of human lung cancer cell line A549, and it can up regulate the expression of p53, Bax and Caspase-3, which may be one of the mechanisms of TNP inducing apoptosis of A549 cells. The experiment also proves that caspase inhibitor can reverse the effect of TNP. TNP inhibits the proliferation of A549 cells.
Genetic alterations in MSS and TMB-H Chinese colorectal cancer patients.
Authors: Ren Shuangyi , Guo Taiyan , You Xia , He Qianru , Zhang Qin , Qi Chuang
Published: June 2021

e15524

Background: Efforts by previous study had provided molecular profile of MSS & TMB-H gastrointestinal (GI) cancers, however, Asian patients were underrepresented in this study. We aim to investigate specific molecular features of Chinese MSS & TMB-H colorectal cancer patients. Methods: FFPE tumor samples from 249 Chinese colorectal cancer patients with MSS & TMB-H (Chinese cohort) were sequencing using a panel targeting 539 cancer-related genes of the human genome. Genomic data from our cohort was compared with publicly available data from 508 MSS & TMB-H colorectal cancer patients from the TCGA dataset (TCGA cohort). TMB was calculated on the two cohorts following the same criteria. TMB-H was defined as the top quartile of all TMB values. Results: In total, 48 (19%) MSS & TMB-H patients were found in Chinese cohort, and 55 (10%) were found in TCGA cohort. Based on the analysis of the genetic alteration profile from our cohort, in MSS & TMB-H colorectal cancer patients, APC (85%), TP53 (81%), KRAS (44%), and LRP1B (378%) as the most commonly altered genes. In TCGA cohort, TTN (84%), APC (80%), TP53 (64%), SYNE1 (51%), and MUC16 (51%) as the most commonly altered genes. On the other hand, the most difference genes between MSS & TMB-H group and MSS/TMB-L group in TCGA cohort were TNN (84% vs. 52%; p = 0.000008), SYNE1 (56% vs. 24%; p = 0.000003), MUC16 (51% vs. 23%; p = 0.00006), FAT4 (47% vs. 16%; p = 0.000002), RYR2 (44%vs. 16%; p = 0.00001). Compared with TCGA cohort, LRP1B (38% vs. 13%; p = 0.0005), TCF7L2 (33% vs. 8%; p = 0.00003), SPTA1 (29% vs. 6%; p = 0.00005), PREX2 (19% vs. 3%; p = 0.0006) were the most difference genes between MSS & TMB-H group and MSS/TMB-L group in Chinese cohort. Conclusions: Our study contributes to the understanding of specific genetic alterations harbored by MSS & TMB-H colorectal cancer patients that could potentially be developed as markers of precision medicine.
Differential gene expression of tight-junction proteins and their correlation with PRSS8 and prognosis in colorectal cancer.
Authors: Yang Wancai , Guo Yongchen , Lu Jim , Bao Yonghua
Published: June 2021

e15548

Background: Intestinal epithelia cells are made up of tight junctions, adheren junctions and desmosomes. As integral membrane proteins, the tight junction proteins (TJPs) claudins (CLDNs) and occludin (OCLN) are the most important TJPs that play a major role in maintaining the integrity of the intestinal epithelia and regulate several key signaling pathways in cancers. Dysregulation of tight junction and adheren junction has been shown to be associated with disruption of mucosa barriers, chronic colitis, early onset of colorectal carcinogenesis, epithelial mesenchymal transition and cancer metastasis. Our recent studies have shown that intestinal conditional knockout of the Press8 (protease serine 8) gene causes disruption of intestinal epithelial homeostasis, spontaneous inflammation and tumorigenesis in mouse intestine. Whether these pathogeneses are resulted from TJPs alterations and their correlation with PRSS8 are largely unknown. Methods: PRSS8 overexpression plasmid was transfected into colon cancer cell line HCT116 cells and proteomics was conducted. The Cancer Genome Atlas colorectal cancer (CRC) data set was deeply mined, and the correlation between TJPs’ alterations, PRSS8 and prognosis was analyzed. Results: In vitro proteomics assay showed that increasing expression of PRSS8 led to differential expression of cellular TJPs and adheren proteins, including upregulation of E-cadherin, TJP1 (ZO-1) and OCLN, and downregulation of RAC1, CDC42, RHOA, CLDND1, ARHGAP1, CTNNB1 and CTNNBL1. TCGA data mining showed differential gene expression of tight junction proteins. For instance, similar as PRSS8, most colonic mucosal TJPs, such as TJP1 (ZO-1), TJP3, OLCN, CLDN7, CLDN8 and PTPRJ, were significantly decreased in CRC tissues (n = 215), compared to normal mucosa (n = 22). Moreover, these reduced expression of TJPs were positively correlated with the reduction of PRSS8 and were inversely associated with prognosis. In contrast, another group of TJPs, such as TJP2, CLDN1, CLDN2 and CLDN12, was significantly increased in CRC tissues in comparison with the normal mucosa. These increases of expression were negatively correlated with PRSS8 expression and poor outcomes. More interestingly, the PTPRJ, a newly identified tumor suppressor, was dramatically reduced in metastatic CRC, compared to the primary CRC. Furthermore, the reduced expression of PTPRJ was linked to poor prognosis in the CRC patients. The underlying mechanisms of regulatory interaction between PRSS8 and TJPs are under investigation. Conclusions: TJPs are differentially expressed in CRC and the alterations were well correlated with PRSS8 and prognosis. Therefore, these two opposite groups of TJPs could be used as biomarkers for the monitoring of early onset colorectal carcinogenesis, progression and for the prediction of prognosis.
Early clinical experience with trifluridine/tipiracil for refractory metastatic colorectal cancer: The ROS study.
Authors: Garcia-Alfonso Pilar , Muñoz Martín Andres J. , Jimenez-Castro Jeronimo , Jiménez-Fonseca Paula , Pericay Carles , Longo Federico , Reyna Carmen , Argiles Guillem , Gonzalez Astorga Beatriz , Gomez-Reina Maria Jose , Ruíz Casado Ana , Rodriguez-Salas Nuria , Lopez-Lopez Rafael , Carmona Bayonas Alberto , Conde-Herrero Veronica , Aranda Enrique
Published: June 2021

e15556

Background: Trifluridine/tipiracil is currently approved for metastatic colorectal cancer (mCRC) refractory to available therapies. However, there is no consensus on factors that predict treatment outcomes in daily practice. We assessed the early clinical experience with trifluridine/tipiracil in Spain and potential survival markers. Methods: This was a retrospective cohort study of mCRC patients who participated in the trifluridine/tipiracil early clinical experience program in Spain. The primary outcome was overall survival (OS). Associations between OS and patient characteristics were assessed using multivariate Cox regression analyses. Results: A total of 379 patients were included in the study. Trifluridine/tipiracil was administered for a median of 3.0 cycles and discontinued mainly due to disease progression (79.2%). The median OS was 7.9 months, with a 12-month OS rate of 30.5%. Cox analyses revealed that the following variables independently favoured OS: ≤2 metastases, no liver metastasis, alkaline phosphatase < 300 IU, trifluridine/tipiracil dose reductions, and neutrophil/lymphocyte ratio < 5. Grade ≥3 toxicities were reported in 141 (37.2%) patients, including mainly afebrile neutropenia (23.2%), anaemia (12.1%), and thrombocytopenia (5.3%). Conclusions: This study supports the real-life efficacy and safety of trifluridine/tipiracil for refractory mCRC and identifies tumour burden, liver metastasis, alkaline phosphatase, dose reductions, and neutrophil/lymphocyte ratio as survival markers.
A single-arm study on the efficacy and safety of regorafenib plus sintilimab as salvage-line treatments in non-MSI-H metastatic colorectal cancer.
Authors: Liu Rui , Wang Xia , Ji Zhi , Deng Ting , Zhang Le , Yang Yuchong , Ning Tao , Bai Ming , Ge Shaohua , Li Hongli , Duan Jingjing , Ba Yi
Published: June 2021

e15560

Background: PD-1 blockade is particularly ineffective in patients with microsatellite stable (MSS) or mismatch repair (MMR)-proficient colorectal cancer (CRC). Regorafenib (R) has been shown to modulate anti-tumor immunity through different mechanisms, including the reduction of tumor-associated macrophages (TAMs) and lymphocyte activation or immunosuppressive cells, such as forkhead box P3 (Foxp3)+ CD25+ regulatory T cells (Tregs). Synergy between R and anti–PD-1/PD-L1 antibodies has been demonstrated in pre-clinical models compared to that of either treatment alone. Accordingly, this study attempted to evaluate the combined activity of regorafenib with an immune checkpoint inhibitor. Methods: This trial was a prospective, open-label, monocentric, nonrandomized, single arm study. This study included patients with non MSI-H mCRC who received R (80 mg QD 3weeks/4) and sintilimab (S)(200 mg every 3 weeks).The primary endpoint was the confirmed objective response rate (ORR).The secondary endpoints were progression free survival (PFS),overall survival (OS),disease control rate (DCR) and safety. Results: As of January 8, 2021, 24 patients (median age 59 years) with mCRC were enrolled and received treatment with R+S. RAS wild type was 50% of all patients. In addition, 83.3% of patients received two prior lines of treatment, while 58.3% had liver metastases at enrollment. Of the 24 patients, the best response was observed to be stable disease(SD) in six patients (25%) and progressive disease (PD)in four patients (16.7%). Another nine (37.5%) patients have yet to be evaluated. In the 15 evaluated patients, the ORR(RECIST version 1.1) was 33.3% , the DCR was 73.3%. Additionally, among the 10 evaluated patients with liver metastases, the ORR was 30% , the DCR was 80%. Among the nine evaluated patients with wild-type populations of k-ras, the ORR and DCR was found to be 44.4% and 66.7%, which was higher than the mutation patients. The median PFS was 4.2 (95% CI, 2.5, NA) months, the median OS was not reached. The most common grade 3/4 adverse events were palmar-plantar erythro-dysesthesia syndrome (4.2%), erythra (4.2%). No death was related to the treatment. Moreover, four (16.7%) patients were subject to at least 1 dose modification or treatment interruption. Conclusions: In this study, the combination of R+S achieved a similar ORR with REGONIVO. Furthermore, this combination was well tolerated and had a manageable safety profile. However, due to the limited sample size, some biases may be present. As a result, we will continue to expand the sample size for future verification. Clinical trial information: NCT04745130.
DNA mismatch repair and microsatellite instability in colorectal tumors: An observational study in the Veterans Affairs Health Care System.
Authors: Klaassen Zachary William Abraham , Waller Justin , Gu Lin , De Hoedt Amanda M. , Wang Tongtong , Amonkar Mayur , Aurora-Garg Deepti , Liaw Kai-Li , Wehn Amy , Albo Daniel , Freedland Stephen J.
Published: June 2021

e15562

Background: Microsatellite instability-high (MSI-H) and deficient mismatch repair (dMMR) cancers exhibit high mutational load and are observed in colorectal carcinomas (CRC). The objectives of this study were to determine the proportion of MSI-H/dMMR in CRC and to describe clinical and demographic characteristics among MSI-H/dMMR and non-MSI-H/dMMR CRC patients receiving standard of care in an equal access health care system. Methods: Using the Veteran Affairs (VA) Healthcare system data, we conducted a retrospective study of patients, aged ≥18 years old, diagnosed with CRC who underwent MSI/MMR testing from January 1, 2010 to December 31, 2018. MSI/MMR testing was defined as having received an MSI status determined by polymerase chain reaction and/or next-generation sequencing test or an MMR status determined by immunohistochemistry test. Median and interquartile range (IQR) were calculated for continuous variables while frequencies and percentages were calculated for categorical variables. Results: A total of 291 patients diagnosed with CRC who underwent MSI/MMR testing between 2010-2018 were identified from VA centers. The majority of patients were white (69.8%) and male (95.5%), with median (IQR) age of 65 (56-70) years at diagnosis. Sixty-four (22.0%) patients had stage I CRC at diagnosis, 84 (28.9%) stage II, 87 (29.9%) stage III, and 45 (15.5%) stage IV; 11 (3.7%) had no stage information. Fifty-four (18.6%) patients were reported to have MSI-H and/or dMMR CRC, with rates similar for MSI-H [17.4% (21/121)] vs. dMMR [19.7% (44/223)] alone. The proportion of MSI-H/dMMR varied by CRC stage, and was more common in stage II (26%) and stage III (23%) than in stage IV (6%). Patients were similar between MSI-H/dMMR and non-MSI-H/dMMR with regards to age at diagnosis, gender, race, and ethnicity. Of 54 patients with MSI-H/dMMR CRC, three had metastatic CRC (mCRC) at diagnosis and seven progressed to mCRC. Among 51 MSI-H/dMMR patients without metastatic disease at diagnosis, 18 (35%) underwent chemotherapy and 44 (86%) underwent curative surgery. A similar pattern was also observed among non-MSI-H/dMMR CRC patients. Conclusions: In this real-world observational study in a VA population, we found MSI-H/dMMR was present in 18.6% of CRC patients who received MSI testing, highest in stage II (26%) and stage III (23%) and lowest in stage IV (6%) disease. Results are consistent with published estimates seen across other populations and geographies. Additional research is needed in larger cohorts of patients to further assess utilization patterns and real-world clinical outcomes of newer treatments (immunotherapies) approved for MSI-H/dMMR CRC.
Efficacy of an anti-EGFR after ctDNA conversion from mutated RAS status of metastatic colorectal cancer: Results of a pilot study.
Authors: Bouchahda Mohamed , Saffroy Raphael , Karaboué Abdoulaye , Hamelin Jocelyne , Innominato Pasquale , Saliba Faouzi , Levi Francis , Bosselut Nelly , Lemoine Antoinette
Published: June 2021

e15574

Background: This pilot study aimed at the evaluation of the efficacy of anti-EGFR therapy in patients with initially RAS-mutated metastatic colorectal cancer, whose liquid biopsy found no RAS mutation after prior chemotherapy failure. Methods: Sixteen patients with RAS-mutated metastatic colorectal cancer in the solid tumor were included, after they had received 1 to 3 prior chemotherapy lines without anti-EGFR. Before inclusion, RAS genotyping was performed in circulating tumor DNA (ctDNA) from liquid biopsy, after a median duration of ̃24 months after the initial RAS status determination. No RAS mutation was detected in the circulating tumor DNA from 9 patients (56%), who then received cetuximab-FOLFIRI. The 7 patients who had persistent RAS mutation in the liquid biopsy (44%) were treated according to standard recommendations without anti-EGFR. Results: The median progression free survival was 8.2 months [95%CL, 4.5 – 11.8] in patients without detectable ctDNA RAS mutation, as compared to 3.5 months [2.1 – 4.9] in the ctDNA mutated patients (p < 0.001). The median overall survival was 22.3 months [17.3 - 27.3] in the patients with undetectable ctDNA RAS mutation, whereas it was 4.7 months [2.6 - 6.7] in those with ctDNA RAS mutation (p = 0.013). These results suggested the efficacy of cetuximab-based chemotherapy in patients with initially RAS mutated metastatic colorectal cancer, who later displayed no detectable ctDNA RAS mutation. Conclusions: The introduction of an anti-EGFR could provide an additional treatment option for patients with metastatic colorectal cancer with apparent conversion of initial RAS mutation, based on ctDNA assessment after prior failure on anti-EGFR-free chemotherapy.
Landscape of COVID-19 vaccine uptake in the colorectal cancer community: Responding to community needs.
Authors: Dwyer Andrea , Marosits Michael , Weltzien Elsa , Garcia Reese , Davis Anjee
Published: June 2021

e15577

Background: The novel coronavirus (COVID-19) has caused numerous disruptions across the cancer prevention and treatment landscape. A model released by the National Cancer Institute (NCI) predicts that delays in care will cause 10,000 excess breast and colorectal cancer deaths over the next 10 years due to the pandemic. Vaccines will play an integral role in colorectal cancer patients and their support systems to return to care and resume ‘normal activities’; but based on anecdotal reports from the oncology and prevention community, there are questions about patients’ willingness to receive vaccines when available. The goal of this analysis was to better understand general uptake of vaccines at various time points, intention to vaccinate when available and what questions and concerns patients have about getting a vaccine. Methods: In January, 2021 Fight Colorectal Cancer (Fight CRC) distributed an online survey to the colorectal cancer community asking about vaccine related questions. The survey was a convenience sample approach distributed through social media channels and targeted emails from mid-January to early February 2021. Virtual focus groups and repeat surveys will be administered in spring of 2021 to further gather detail about the uptake of the vaccine, including barriers and facilitators to care. Results: In total, 201 individuals responded to the survey (survivor = 77%, family member = 11%, caregiver/friend = 8% other = 3%). The colorectal cancer patient sample was composed mostly of later stage patients (stage III and IV = 77%). Approximately 30% of patients reported vaccine uptake, 81% noted they would likely get vaccinated when a vaccine became available to them. Of all the patients, 16% noted they would need more information about the vaccine before deciding if they would be vaccinated. The majority indicated needing tips to discuss receiving the vaccine with their doctor, including impact on treatment, and the top questions patients have are: 1) Is the vaccine safe? 2) Will the vaccine interrupt my cancer treatment care? Conclusions: People with cancer face unique challenges since the pandemic, including treatment disruptions. Even with a vaccine, not all patients have access or are convinced they will receive the vaccine when it becomes available to them. Understanding patient needs and how to respond to ensure patients receive the most credible information to make informed decisions is critical.