bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Cost-effectiveness of Human Papillomavirus Self-collection Intervention on Cervical Cancer Screening Uptake among Underscreened U.S. Persons with a Cervix
Authors: Spees Lisa P. , Biddell Caitlin B. , Smith Jennifer S. , Des Marais Andrea C. , Hudgens Michael G. , Sanusi Busola , Jackson Sarah , Brewer Noel T. , Wheeler Stephanie B.
Published: August 2023

AbstractBackground:
We evaluate the cost-effectiveness of human papillomavirus (HPV) self-collection (followed by scheduling assistance for those who were HPV+ or inconclusive) compared with scheduling assistance only and usual care among underscreened persons with a cervix (PWAC).
Methods:
A decision tree analysis was used to estimate the incremental cost-effectiveness ratios (ICER), or the cost per additional PWAC screened, from the Medicaid/state and clinic perspectives. A hypothetical cohort represented 90,807 low-income, underscreened individuals. Costs and health outcomes were derived from the MyBodyMyTest-3 randomized trial except the usual care health outcomes were derived from literature. We performed probabilistic sensitivity analyses (PSA) to evaluate model uncertainty.
Results:
Screening uptake was highest in the self-collection alternative (n = 65,721), followed by the scheduling assistance alternative (n = 34,003) and usual care (n = 18,161). The self-collection alternative costs less and was more effective than the scheduling assistance alternative from the Medicaid/state perspective. Comparing the self-collection alternative with usual care, the ICERs were $284 per additional PWAC screened from the Medicaid/state perspective and $298 per additional PWAC screened from the clinic perspective. PSAs demonstrated that the self-collection alternative was cost-effective compared with usual care at a willingness-to-pay threshold of $300 per additional PWAC screened in 66% of simulations from the Medicaid/state perspective and 58% of simulations from the clinic perspective.
Conclusions:
Compared with usual care and scheduling assistance, mailing HPV self-collection kits to underscreened individuals appears to be cost-effective in increasing screening uptake.
Impact:
This is the first analysis to demonstrate the cost-effectiveness of mailed self-collection in the United States.
Data from Associations between Etiologic or Prognostic Tumor Tissue Markers and Neighborhood Contextual Factors in Male Health Professionals Diagnosed with Prostate Cancer
Authors: Iyer Hari S. , Kensler Kevin H. , Vaselkiv Jane B. , Stopsack Konrad H. , Roscoe Charlotte , Bandera Elisa V. , Qin Bo , Jang Thomas L. , Lotan Tamara L. , James Peter , Hart Jaime E. , Mucci Lorelei A. , Laden Francine , Rebbeck Timothy R.
Published: August 2023

AbstractBackground:
There is growing evidence that unfavorable neighborhood contexts may influence prostate cancer progression. Whether these associations may be explained in part by differences in tumor-level somatic alterations remain unclear.
Methods:
Data on tumor markers (PTEN, p53, ERG, and SPINK1) were obtained from 1,157 participants with prostate cancer in the Health Professionals Follow-up Study. Neighborhood greenness, socioeconomic status, and the income Index of Concentration at Extremes were obtained from satellite and census data and linked to participants’ address at diagnosis and at study enrollment. Exposures were scaled to an interquartile range and modeled as tertiles. Bivariate associations between tertiles of neighborhood factors and tumor markers were assessed in covariate adjusted logistic regression models to estimate ORs and 95% confidence intervals.
Results:
There was no association between any of the neighborhood contextual factors and PTEN, p53, ERG, or SPINK1 in bivariate or multivariable adjusted models. Results were generally consistent when modeling exposure using exposure at diagnosis or at study enrollment.
Conclusions:
In this multilevel study of men with prostate cancer, we found no evidence of associations between neighborhood context and tumor tissue markers.
Impact:
Our results provide some of the first empirical data in support of the hypothesis that prostate cancer risk conferred by tumor tissue markers may arise independently of underlying neighborhood context. Prospective studies in more diverse populations are needed to confirm these findings.
Data from Field Synopsis of Environmental and Genetic Risk Factors of Sporadic Early-Onset Colorectal Cancer and Advanced Adenoma
Authors: Zhang Rongqi , Boakye Daniel , Yang Nan , Zhou Xuan , Zhou Yajing , Jiang Fangyuan , Yu Lili , Wang Lijuan , Sun Jing , Yuan Shuai , Chen Jie , Hamilton Ashleigh C. , Coleman Helen G. , Larsson Susanna C. , Little Julian , Dunlop Malcolm G. , Giovannucci Edward L. , Theodoratou Evropi , Li Xue
Published: August 2023

AbstractBackground:
To systematically appraise and synthesize available epidemiologic evidence on the associations of environmental and genetic factors with the risk of sporadic early-onset colorectal cancer (EOCRC) and early-onset advanced colorectal adenoma (EOCRA).
Methods:
Multiple databases were comprehensively searched to identify eligible observational studies. Genotype data from UK Biobank were incorporated to examine their associations with EOCRC in a nested case–control design. Meta-analyses of environmental risk factors were performed, and the strength of evidence was graded based on predefined criteria. Meta-analyses of genetic associations were conducted using the allelic, recessive, and dominant models, respectively.
Results:
A total of 61 studies were included, reporting 120 environmental factors and 62 genetic variants. We found 12 risk factors (current overweight, overweight in adolescence, high waist circumference, smoking, alcohol, sugary beverages intake, sedentary behavior, red meat intake, family history of colorectal cancer, hypertension, hyperlipidemia, and metabolic syndrome) and three protective factors (vitamin D, folate, and calcium intake) for EOCRC or EOCRA. No significant associations between the examined genetic variants and EOCRC risk were observed.
Conclusions:
Recent data indicate that the changing patterns of traditional colorectal cancer risk factors may explain the rising incidence of EOCRC. However, research on novel risk factors for EOCRC is limited; therefore, we cannot rule out the possibility of EOCRC having different risk factors than late-onset colorectal cancer (LOCRC).
Impact:
The potential for the identified risk factors to enhance the identification of at-risk groups for personalized EOCRC screening and prevention and for the prediction of EOCRC risk should be comprehensively addressed by future studies.
Figure S3 from Immunogenomic Landscape of Neuroendocrine Prostate Cancer
Authors: Bhinder Bhavneet , Ferguson Alison , Sigouros Michael , Uppal Manik , Elsaeed Ahmed G. , Bareja Rohan , Alnajar Hussein , Eng Kenneth Wha , Conteduca Vincenza , Sboner Andrea , Mosquera Juan Miguel , Elemento Olivier , Beltran Himisha
Published: August 2023

Suppl Figure 3. Identification of gene modules associated with NEPC T-cell immune classes.
Supplementary Table S1 from Targeting BET Proteins Downregulates miR-33a To Promote Synergy with PIM Inhibitors in CMML
Authors: Letson Christopher T. , Balasis Maria E. , Newman Hannah , Binder Moritz , Vedder Alexis , Kinose Fumi , Ball Markus , Kruer Traci , Quintana Ariel , Lasho Terra L. , Finke Christy M. , Almada Luciana L. , Grants Jennifer M. , Zhang Guolin , Fernandez-Zapico Martin E. , Gaspar-Maia Alexandre , Lancet Jeffrey , Komrokji Rami , Haura Eric , Sallman David A. , Reuther Gary W. , Karsan Aly , Rix Uwe , Patnaik Mrinal M. , Padron Eric
Published: August 2023

Raw data associated with drug screen performed in Figure 1A.
Supplementary Figure S7 from Targeting BET Proteins Downregulates miR-33a To Promote Synergy with PIM Inhibitors in CMML
Authors: Letson Christopher T. , Balasis Maria E. , Newman Hannah , Binder Moritz , Vedder Alexis , Kinose Fumi , Ball Markus , Kruer Traci , Quintana Ariel , Lasho Terra L. , Finke Christy M. , Almada Luciana L. , Grants Jennifer M. , Zhang Guolin , Fernandez-Zapico Martin E. , Gaspar-Maia Alexandre , Lancet Jeffrey , Komrokji Rami , Haura Eric , Sallman David A. , Reuther Gary W. , Karsan Aly , Rix Uwe , Patnaik Mrinal M. , Padron Eric
Published: August 2023

Supplemental Figure 7 shows clonogenicity data associated with 6A broken down by patient sample and a non-transplanted control sample stained with CD45 corresponding to Figure 6E.
Supplementary Figure S6 from Targeting BET Proteins Downregulates miR-33a To Promote Synergy with PIM Inhibitors in CMML
Authors: Letson Christopher T. , Balasis Maria E. , Newman Hannah , Binder Moritz , Vedder Alexis , Kinose Fumi , Ball Markus , Kruer Traci , Quintana Ariel , Lasho Terra L. , Finke Christy M. , Almada Luciana L. , Grants Jennifer M. , Zhang Guolin , Fernandez-Zapico Martin E. , Gaspar-Maia Alexandre , Lancet Jeffrey , Komrokji Rami , Haura Eric , Sallman David A. , Reuther Gary W. , Karsan Aly , Rix Uwe , Patnaik Mrinal M. , Padron Eric
Published: August 2023

Supplemental Figure 6 shows PIM1 levels after increasing concentrations of BETi
Supplementary Figure S5 from Targeting BET Proteins Downregulates miR-33a To Promote Synergy with PIM Inhibitors in CMML
Authors: Letson Christopher T. , Balasis Maria E. , Newman Hannah , Binder Moritz , Vedder Alexis , Kinose Fumi , Ball Markus , Kruer Traci , Quintana Ariel , Lasho Terra L. , Finke Christy M. , Almada Luciana L. , Grants Jennifer M. , Zhang Guolin , Fernandez-Zapico Martin E. , Gaspar-Maia Alexandre , Lancet Jeffrey , Komrokji Rami , Haura Eric , Sallman David A. , Reuther Gary W. , Karsan Aly , Rix Uwe , Patnaik Mrinal M. , Padron Eric
Published: August 2023

Supplemental Figure 5 contains ChIP-seq tracks of all individual samples corresponding to Figure 5D.
Supplementary Figure S3 from Targeting BET Proteins Downregulates miR-33a To Promote Synergy with PIM Inhibitors in CMML
Authors: Letson Christopher T. , Balasis Maria E. , Newman Hannah , Binder Moritz , Vedder Alexis , Kinose Fumi , Ball Markus , Kruer Traci , Quintana Ariel , Lasho Terra L. , Finke Christy M. , Almada Luciana L. , Grants Jennifer M. , Zhang Guolin , Fernandez-Zapico Martin E. , Gaspar-Maia Alexandre , Lancet Jeffrey , Komrokji Rami , Haura Eric , Sallman David A. , Reuther Gary W. , Karsan Aly , Rix Uwe , Patnaik Mrinal M. , Padron Eric
Published: August 2023

Supplemental Figure 3 shows endogenous PIM1 levels in SKM1 WT and overexpressing cells and BETi/PIMi sensitivity correlation in PIM1 overexpressing cells.
Supplementary Table S7 from Determinants of Survival with Combined HER2 and PD-1 Blockade in Metastatic Esophagogastric Cancer
Authors: Maron Steven B. , Chatila Walid , Walch Henry , Chou Joanne F. , Ceglia Nicholas , Ptashkin Ryan , Do Richard Kinh Gian , Paroder Viktoriya , Pandit-Taskar Neeta , Lewis Jason S. , Biachi De Castria Tiago , Sabwa Shalom , Socolow Fiona , Feder Lara , Thomas Jasmine , Schulze Isabell , Kim Kwanghee , Elzein Arijh , Bojilova Viktoria , Zatzman Matthew , Bhanot Umesh , Nagy Rebecca J. , Lee Jeeyun , Simmons Marc , Segal Michal , Ku Geoffrey Yuyat , Ilson David H. , Capanu Marinela , Hechtman Jaclyn F. , Merghoub Taha , Shah Sohrab , Schultz Nikolaus , Solit David B. , Janjigian Yelena Y.
Published: August 2023

Univariable Cox Proportional Hazard for PFS in HER2-targeted retrospective cohort.
Supplementary Table S4 from Determinants of Survival with Combined HER2 and PD-1 Blockade in Metastatic Esophagogastric Cancer
Authors: Maron Steven B. , Chatila Walid , Walch Henry , Chou Joanne F. , Ceglia Nicholas , Ptashkin Ryan , Do Richard Kinh Gian , Paroder Viktoriya , Pandit-Taskar Neeta , Lewis Jason S. , Biachi De Castria Tiago , Sabwa Shalom , Socolow Fiona , Feder Lara , Thomas Jasmine , Schulze Isabell , Kim Kwanghee , Elzein Arijh , Bojilova Viktoria , Zatzman Matthew , Bhanot Umesh , Nagy Rebecca J. , Lee Jeeyun , Simmons Marc , Segal Michal , Ku Geoffrey Yuyat , Ilson David H. , Capanu Marinela , Hechtman Jaclyn F. , Merghoub Taha , Shah Sohrab , Schultz Nikolaus , Solit David B. , Janjigian Yelena Y.
Published: August 2023

Plasma ctDNA Alterations by Source.
Supplementary Table S3 from Determinants of Survival with Combined HER2 and PD-1 Blockade in Metastatic Esophagogastric Cancer
Authors: Maron Steven B. , Chatila Walid , Walch Henry , Chou Joanne F. , Ceglia Nicholas , Ptashkin Ryan , Do Richard Kinh Gian , Paroder Viktoriya , Pandit-Taskar Neeta , Lewis Jason S. , Biachi De Castria Tiago , Sabwa Shalom , Socolow Fiona , Feder Lara , Thomas Jasmine , Schulze Isabell , Kim Kwanghee , Elzein Arijh , Bojilova Viktoria , Zatzman Matthew , Bhanot Umesh , Nagy Rebecca J. , Lee Jeeyun , Simmons Marc , Segal Michal , Ku Geoffrey Yuyat , Ilson David H. , Capanu Marinela , Hechtman Jaclyn F. , Merghoub Taha , Shah Sohrab , Schultz Nikolaus , Solit David B. , Janjigian Yelena Y.
Published: August 2023

Correlation of 89Zr PET Uptake and HER2 Status
Supplementary Figure S6 from Determinants of Survival with Combined HER2 and PD-1 Blockade in Metastatic Esophagogastric Cancer
Authors: Maron Steven B. , Chatila Walid , Walch Henry , Chou Joanne F. , Ceglia Nicholas , Ptashkin Ryan , Do Richard Kinh Gian , Paroder Viktoriya , Pandit-Taskar Neeta , Lewis Jason S. , Biachi De Castria Tiago , Sabwa Shalom , Socolow Fiona , Feder Lara , Thomas Jasmine , Schulze Isabell , Kim Kwanghee , Elzein Arijh , Bojilova Viktoria , Zatzman Matthew , Bhanot Umesh , Nagy Rebecca J. , Lee Jeeyun , Simmons Marc , Segal Michal , Ku Geoffrey Yuyat , Ilson David H. , Capanu Marinela , Hechtman Jaclyn F. , Merghoub Taha , Shah Sohrab , Schultz Nikolaus , Solit David B. , Janjigian Yelena Y.
Published: August 2023

HER2 heterogeneity and RTK alterations are more frequent among patients with shorter PFS. HER2 testing and tissue/plasma ctDNA NGS upon progression demonstrate that 8 of 16 (50%) of patients had HER2 negative tumors post-treatment, and 2 ERBB2 amplified tumors pre-treatment were non-amplified post-treatment. Additionally, frequent alterations in PI3K, cell cycle proteins, Ras-Raf, EGFR, FGFR1/2, and MET were found upon progression, and potentially associated with treatment resistance.
Supplementary Figure S3 from Determinants of Survival with Combined HER2 and PD-1 Blockade in Metastatic Esophagogastric Cancer
Authors: Maron Steven B. , Chatila Walid , Walch Henry , Chou Joanne F. , Ceglia Nicholas , Ptashkin Ryan , Do Richard Kinh Gian , Paroder Viktoriya , Pandit-Taskar Neeta , Lewis Jason S. , Biachi De Castria Tiago , Sabwa Shalom , Socolow Fiona , Feder Lara , Thomas Jasmine , Schulze Isabell , Kim Kwanghee , Elzein Arijh , Bojilova Viktoria , Zatzman Matthew , Bhanot Umesh , Nagy Rebecca J. , Lee Jeeyun , Simmons Marc , Segal Michal , Ku Geoffrey Yuyat , Ilson David H. , Capanu Marinela , Hechtman Jaclyn F. , Merghoub Taha , Shah Sohrab , Schultz Nikolaus , Solit David B. , Janjigian Yelena Y.
Published: August 2023

Response to pembrolizumab and trastuzumab induction according to pre-treatment 89Zr-trastuzumab PET avidity.
Supplementary Data S1 from Determinants of Survival with Combined HER2 and PD-1 Blockade in Metastatic Esophagogastric Cancer
Authors: Maron Steven B. , Chatila Walid , Walch Henry , Chou Joanne F. , Ceglia Nicholas , Ptashkin Ryan , Do Richard Kinh Gian , Paroder Viktoriya , Pandit-Taskar Neeta , Lewis Jason S. , Biachi De Castria Tiago , Sabwa Shalom , Socolow Fiona , Feder Lara , Thomas Jasmine , Schulze Isabell , Kim Kwanghee , Elzein Arijh , Bojilova Viktoria , Zatzman Matthew , Bhanot Umesh , Nagy Rebecca J. , Lee Jeeyun , Simmons Marc , Segal Michal , Ku Geoffrey Yuyat , Ilson David H. , Capanu Marinela , Hechtman Jaclyn F. , Merghoub Taha , Shah Sohrab , Schultz Nikolaus , Solit David B. , Janjigian Yelena Y.
Published: August 2023

Supplemental Data, Spreadsheet
Data from Combination ATR (ceralasertib) and PARP (olaparib) Inhibitor (CAPRI) Trial in Acquired PARP Inhibitor–Resistant Homologous Recombination–Deficient Ovarian Cancer
Authors: Wethington Stephanie L. , Shah Payal D. , Martin Lainie , Tanyi Janos L. , Latif Nawar , Morgan Mark , Torigian Drew A. , Rodriguez Diego , Smith Simon A. , Dean Emma , Domchek Susan M. , Drapkin Ronny , Shih Ie-Ming , Brown Eric J. , Hwang Wei-Ting , Armstrong Deborah K. , Gaillard Stephanie , Giuntoli Robert , Simpkins Fiona
Published: August 2023

AbstractPurpose:
Addition of ataxia telangiectasia and Rad3-related kinase inhibitors (ATRi) to PARP inhibitors (PARPi) overcomes PARPi resistance in high-grade serous ovarian cancer (HGSOC) cell and mouse models. We present the results of an investigator-initiated study of combination PARPi (olaparib) and ATRi (ceralasertib) in patients with acquired PARPi-resistant HGSOC.
Patients and Methods:
Eligible patients had recurrent, platinum-sensitive BRCA1/2 mutated or homologous recombination (HR)–deficient (HRD) HGSOC and clinically benefited from PARPi (response by imaging/CA-125 or duration of maintenance therapy; > 12 months first-line or > 6 months ≥ second-line) before progression. No intervening chemotherapy was permitted. Patients received olaparib 300 mg twice daily and ceralasertib 160 mg daily on days 1 to 7 of a 28-day cycle. Primary objectives were safety and objective response rate (ORR).
Results:
Thirteen patients enrolled were evaluable for safety and 12 for efficacy; 62% (n = 8) had germline BRCA1/2 mutations, 23% (n = 3) somatic BRCA1/2 mutations, and 15% (n = 2) tumors with positive HRD assay. Prior PARPi indication was treatment for recurrence (54%, n = 7), second-line maintenance (38%, n = 5) and first-line treatment with carboplatin/paclitaxel (8%, n = 1). There were 6 partial responses yielding an ORR of 50% (95% confidence interval, 0.15–0.72). Median treatment duration was 8 cycles (range 4–23+). Grade (G) 3/4 toxicities were 38% (n = 5); 15% (n = 2) G3 anemia, 23% (n = 3) G3 thrombocytopenia, 8% (n = 1) G4 neutropenia. Four patients required dose reductions. No patient discontinued treatment due to toxicity.
Conclusions:
Combination olaparib and ceralasertib is tolerable and shows activity in HR-deficient platinum-sensitive recurrent HGSOC that benefited and then progressed with PARPi as the penultimate regimen. These data suggest that ceralasertib resensitizes PARPi-resistant HGSOCs to olaparib, warranting further investigation.
Data from HLA Class II Loss and JAK1/2 Deficiency Coevolve in Melanoma Leading to CD4 T-cell and IFNγ Cross-Resistance
Authors: Stupia Simone , Heeke Christina , Brüggemann Alicia , Zaremba Anne , Thier Beatrice , Kretz Julia , Sucker Antje , Philip Manuel , Zelinskyy Gennadiy , Ferrone Soldano , Roesch Alexander , Horn Susanne , Hadaschik Eva , Schadendorf Dirk , Trilling Mirko , Dittmer Ulf , Griewank Klaus , Zhao Fang , Paschen Annette
Published: August 2023

AbstractPurpose:
Recent studies have demonstrated HLA class II (HLA-II)–dependent killing of melanoma cells by cytotoxic CD4 T cells. We investigated evolution of HLA-II–loss tumors that escape cytotoxic CD4 T-cell activity and contribute to immunotherapy resistance.
Experimental Design:
Melanoma cells from longitudinal metastases were studied for constitutive and IFN-inducible HLA-II expression, sensitivity towards autologous CD4 T cells, and immune evasion by HLA-II loss. Clinical significance of HLA-II–low tumors was determined by analysis of transcriptomic data sets from patients with immune checkpoint blockade (ICB).
Results:
Analysis of longitudinal samples revealed strong intermetastatic heterogeneity in melanoma cell–intrinsic HLA-II expression and subclonal HLA-II loss. Tumor cells from early lesions either constitutively expressed HLA-II, sensitizing to cytotoxic CD4 T cells, or induced HLA-II and gained CD4 T-cell sensitivity in the presence of IFNγ. In contrast, late outgrowing subclones displayed a stable CD4 T-cell–resistant HLA-II–loss phenotype. These cells lacked not only constitutive but also IFNγ-inducible HLA-II due to JAK1/2-STAT1 pathway inactivation. Coevolution of JAK1/2 deficiency and HLA-II loss established melanoma cross-resistance to IFNγ and CD4 T cells, as detected in distinct stage IV metastases. In line with their immune-evasive phenotype, HLA-II–low melanomas showed reduced CD4 T-cell infiltrates and correlated with disease progression under ICB.
Conclusions:
Our study links melanoma resistance to CD4 T cells, IFNγ, and ICB at the level of HLA-II, highlighting the significance of tumor cell–intrinsic HLA-II antigen presentation in disease control and calling for strategies to overcome its downregulation for improvement of patient outcome.
Data from Antitumor Efficacy of the Novel KIT Inhibitor IDRX-42 (Formerly M4205) in Patient- and Cell Line–Derived Xenograft Models of Gastrointestinal Stromal Tumor (GIST)
Authors: De Sutter Luna , Wozniak Agnieszka , Verreet Jasper , Vanleeuw Ulla , De Cock Lore , Linde Nina , Drechsler Christine , Esdar Christina , Sciot Raf , Schöffski Patrick
Published: August 2023

AbstractPurpose:
The majority of gastrointestinal stromal tumors (GIST) are driven by constitutively activated KIT/PDGFRA kinases and are susceptible to treatment with tyrosine kinase inhibitors. During treatment, most of these tumors will develop secondary mutations in KIT or PDGFRA inducing drug resistance, so there is an unmet need for novel therapies. We tested the efficacy of IDRX-42, a novel selective KIT inhibitor with high activity toward the most relevant KIT mutations, in 4 GIST xenograft models.
Experimental Design:
NMRI nu/nu mice were transplanted with patient-derived GIST xenograft models UZLX-GIST9 (KIT:p.P577del;W557LfsX5;D820G), UZLX-GIST2B (KIT:p.A502_Y503dup), UZLX-GIST25 (KIT:p.K642E), and the cell line–derived model GIST882 (KIT:p.K642E). Mice were treated daily with vehicle (control), imatinib (100 mg/kg), sunitinib (20 mg/kg), avapritinib (5 mg/kg), or IDRX-42 (10 mg/kg, 25 mg/kg). Efficacy was assessed by tumor volume evolution, histopathology, grading of histologic response, and IHC. The Kruskal–Wallis and Wilcoxon matched-pairs tests were used for statistical analysis, with P < 0.05 considered as significant.
Results:
IDRX-42 (25 mg/kg) caused tumor volume shrinkage in UZLX-GIST25, GIST882, and UZLX-GIST2B, with a relative decrease to 45.6%, 57.3%, and 35.1% on the last day as compared with baseline, and tumor growth delay (160.9%) compared with control in UZLX-GIST9. Compared with controls, IDRX-42 (25 mg/kg) induced a significant decrease in mitosis. In UZLX-GIST25 and GIST882 grade 2–4 histologic response with myxoid degeneration was observed in all IDRX-42 (25 mg/kg)-treated tumors.
Conclusions:
IDRX-42 showed significant antitumor activity in patient- and cell line–derived GIST xenograft models. The novel kinase inhibitor induced volumetric responses, decreased mitotic activity, and had antiproliferative effects. In models with KIT exon 13 mutation IDRX-42 induced characteristic myxoid degeneration.
Data from Immunogenomic Landscape of Neuroendocrine Prostate Cancer
Authors: Bhinder Bhavneet , Ferguson Alison , Sigouros Michael , Uppal Manik , Elsaeed Ahmed G. , Bareja Rohan , Alnajar Hussein , Eng Kenneth Wha , Conteduca Vincenza , Sboner Andrea , Mosquera Juan Miguel , Elemento Olivier , Beltran Himisha
Published: August 2023

AbstractPurpose:
Patients with neuroendocrine prostate cancer (NEPC) are often managed with immunotherapy regimens extrapolated from small-cell lung cancer (SCLC). We sought to evaluate the tumor immune landscape of NEPC compared with other prostate cancer types and SCLC.
Experimental Design:
In this retrospective study, a cohort of 170 patients with 230 RNA-sequencing and 104 matched whole-exome sequencing data were analyzed. Differences in immune and stromal constituents, frequency of genomic alterations, and associations with outcomes were evaluated.
Results:
In our cohort, 36% of the prostate tumors were identified as CD8+ T-cell inflamed, whereas the remaining 64% were T-cell depleted. T-cell–inflamed tumors were enriched in anti-inflammatory M2 macrophages and exhausted T cells and associated with shorter overall survival relative to T-cell–depleted tumors (HR, 2.62; P < 0.05). Among all prostate cancer types in the cohort, NEPC was identified to be the most immune depleted, wherein only 9 out of the 36 total NEPC tumors were classified as T-cell inflamed. These inflamed NEPC cases were enriched in IFN gamma signaling and PD-1 signaling compared with other NEPC tumors. Comparison of NEPC with SCLC revealed that NEPC had poor immune content and less mutations compared with SCLC, but expression of checkpoint genes PD-L1 and CTLA-4 was comparable between NEPC and SCLC.
Conclusions:
NEPC is characterized by a relatively immune-depleted tumor immune microenvironment compared with other primary and metastatic prostate adenocarcinoma except in a minority of cases. These findings may inform development of immunotherapy strategies for patients with advanced prostate cancer.
Data from Maveropepimut-S, a DPX-Based Immune-Educating Therapy, Shows Promising and Durable Clinical Benefit in Patients with Recurrent Ovarian Cancer, a Phase II Trial
Authors: Dorigo Oliver , Oza Amit M. , Pejovic Tanja , Ghatage Prafull , Ghamande Sharad , Provencher Diane , MacDonald Lisa D. , Torrey Heather , Kaliaperumal Valarmathy , Ebrahimizadeh Walead , Hirsch Heather A. , Bramhecha Yogesh , Villella Jeannine , Fiset Stephan
Published: August 2023

AbstractPurpose:
Patients with platinum-resistant ovarian cancer respond poorly to existing therapies. Hence there is a need for more effective treatments.
Patients and Methods:
The DeCidE1 trial is a multicenter, randomized, open-label, single-arm phase II study to evaluate the safety and effectiveness of maveropepimut-S with cyclophosphamide in patients with recurrent ovarian cancer. Median follow-up for evaluable subjects was 4.4 months. Data were collected from March 2019 to June 2021. Subjects received two injections of 0.25 mL maveropepimut-S 3 weeks apart, followed by one 0.1-mL doses, every 8 weeks up to progression. Oral cyclophosphamide, 50 mg twice daily, was administered in repeating weekly on and off cycles.
Results:
Twenty-two patients were enrolled. Median age was 58 years (38–78 years). Among the evaluable population, the objective response rate (ORR) was 21% [90% confidence interval (CI), 7.5%–41.9%], with a disease control rate (DCR) of 63% (90% CI, 41.8%–81.3%), including 4 (21%) patients with partial responses, 8 (42%) stable disease, and 7 (37%) progressive disease. The ORRs were consistent across subgroups based on platinum sensitivity, and DCR was higher in the platinum-resistant subpopulation. Four SD patients maintained clinical benefit up to 25 months. Most treatment-related adverse events (TRAE) were grade 1 and 2 (87% of unique events). Most common AEs were injection site reactions. Eight subjects reported grade 3 and no grade 4 AEs. Survivin-specific T-cell responses were observed in treated patients with clinical benefit.
Conclusions:
Maveropepimut-S with intermittent low-dose cyclophosphamide is well-tolerated, with clinical benefit for patients with recurrent ovarian cancer. Observed responses are irrespective of the platinum status.
Data from Phase 1 Study of JNJ-64619178, a Protein Arginine Methyltransferase 5 Inhibitor, in Advanced Solid Tumors
Authors: Vieito Maria , Moreno Victor , Spreafico Anna , Brana Irene , Wang Judy S. , Preis Meir , Hernandez-Guerrero Tatiana , Genta Sofia , Hansen Aaron R. , Doger Bernard , Galvao Vladimir , Lenox Laurie , Brown Regina J. , Kalota Anna , Mehta Jaydeep , Pastore Friederike , Patel Bharvin , Mistry Pankaj , Gu Junchen , Lauring Josh , Patel Manish R.
Published: August 2023

Abstract
Purpose: In this first-in-human, Phase 1, open-label, multicenter study, we evaluated JNJ-64619178, a selective and potent PRMT5 inhibitor, in patients with advanced malignant solid tumors or non-Hodgkin lymphomas. The primary objective was to evaluate the safety and to identify a recommended Phase 2 dose (RP2D) of JNJ-64619178. Patients and Methods: Adult patients with treatment-refractory advanced solid tumors or non-Hodgkin lymphomas and measurable disease received escalating doses of JNJ-64619178 following two schedules (Schedule A: 14 days on/7 days off; Schedule B: every day on a 21-day cycle). Safety, pharmacokinetics (PK), pharmacodynamics, and clinical activity were evaluated. Results: Ninety patients received JNJ-64619178. Thrombocytopenia was identified as the only dose-limiting toxicity. JNJ-64619178 showed dose-proportional PK and robust target engagement, as measured by plasma symmetric dimethylarginine, across all dose levels. The objective response rate was 5.6% (5 of 90). Patients with adenoid cystic carcinoma (ACC) had an ORR of 11.5% (3 of 26) and a median progression-free survival of 19.1 months. Conclusions: JNJ-64619178 demonstrated manageable dose-dependent toxicity and preliminary evidence of antitumor activity in ACC and other tumor types. Plasma exposure was dose dependent, and target inhibition was maintained with intermittent and continuous dosing. Based on safety, clinical activity, PK, and PD findings, two provisional RP2Ds were selected: 1.5 mg intermittently and 1.0 mg once daily. Aside from ACC, clinical benefit was limited, and biomarkers to enrich for responsiveness to PRMT5 inhibition will be needed for further development.
Figure S3 from Bromo- and Extra-Terminal Domain Inhibitors Induce Mitochondrial Stress in Pancreatic Ductal Adenocarcinoma
Authors: Rana Manjul , Kansal Rita G. , Bisunke Bijay , Fang Jie , Shibata David , Bajwa Amandeep , Yang Jun , Glazer Evan S.
Published: August 2023

Figure S3
Figure S1 from Bromo- and Extra-Terminal Domain Inhibitors Induce Mitochondrial Stress in Pancreatic Ductal Adenocarcinoma
Authors: Rana Manjul , Kansal Rita G. , Bisunke Bijay , Fang Jie , Shibata David , Bajwa Amandeep , Yang Jun , Glazer Evan S.
Published: August 2023

updated figure S1
Supplementary Table S3 from Schlafen 11 (SLFN11) Kills Cancer Cells Undergoing Unscheduled Re-replication
Authors: Murai Junko , Ceribelli Michele , Fu Haiqing , Redon Christophe E. , Jo Ukhyun , Murai Yasuhisa , Aladjem Mirit I. , Thomas Craig J. , Pommier Yves
Published: August 2023

Data for Figure 4B
Supplementary Figure S4 from Schlafen 11 (SLFN11) Kills Cancer Cells Undergoing Unscheduled Re-replication
Authors: Murai Junko , Ceribelli Michele , Fu Haiqing , Redon Christophe E. , Jo Ukhyun , Murai Yasuhisa , Aladjem Mirit I. , Thomas Craig J. , Pommier Yves
Published: August 2023

Figure S4
Supplementary Figure S1 from Schlafen 11 (SLFN11) Kills Cancer Cells Undergoing Unscheduled Re-replication
Authors: Murai Junko , Ceribelli Michele , Fu Haiqing , Redon Christophe E. , Jo Ukhyun , Murai Yasuhisa , Aladjem Mirit I. , Thomas Craig J. , Pommier Yves
Published: August 2023

Figure S1
Figure S.1 from ABBV-184: A Novel Survivin-specific TCR/CD3 Bispecific T-cell Engager is Active against Both Solid Tumor and Hematologic Malignancies
Authors: Chervin Adam S. , Stone Jennifer D. , Konieczna Iwona , Calabrese Kelly M. , Wang Ningyan , Haribhai Dipica , Dong Feng , White Michael K. , Rodriguez Luis E. , Bukofzer Gail T. , Ellis Paul A. , Cosgrove Cormac , Hecquet Claudie , Clarin Jerry D. , Palma Joann P. , Reilly Edward B.
Published: August 2023

A prostate tumor cell line (PC3M-A2/beta 2M) was inoculated subcutaneously in the right flank of CD34-humanized NSG mice. Mice were treated intravenously at indicated time points with either vehicle or with an ABBV-184 precursor molecule, and tumor size was monitored. Tumors experienced transient regression and growth inhibition prior to harvest for analysis of tumor-infiltrating immune cells.
Supplementary Figure 4 from Vincristine Enhances the Efficacy of MEK Inhibitors in Preclinical Models of KRAS-mutant Colorectal Cancer
Authors: Ghosh Susmita , Fan Fan , Powell Reid T. , Roszik Jason , Park Yong Sung , Stephan Clifford , Sebastian Manu , Tan Lin , Sorokin Alexey V. , Lorenzi Philip L. , Kopetz Scott , Ellis Lee M. , Bhattacharya Rajat
Published: August 2023

Supplementary Figure 4 shows that the combination of trametinib and vincristine is well tolerated in mice.
Supplementary Table S8 from Preclinical Evaluation of 9MW2821, a Site-Specific Monomethyl Auristatin E–based Antibody–Drug Conjugate for Treatment of Nectin-4–expressing Cancers
Authors: Zhou Wei , Fang Peng , Yu Dongan , Ren Hongyuan , You Meng , Yin Long , Mei Fei , Zhu Huikai , Wang Zhenzhen , Xu Hui , Cao Yuxia , Sun Xiaowei , Xu Xiaohong , Bi Jianjun , Wang Jin , Ma Lanping , Wang Xin , Chen Lin , Zhang Yongliang , Cen Xiaowei , Zhu Xi , Lou Liguang , Liu Datao , Tan Xiaoding , Yang Jinliang , Meng Tao , Shen Jingkang
Published: August 2023

Binding affinity and kinetics based on Bio Layer Interferometry
Supplementary Table S6 from Preclinical Evaluation of 9MW2821, a Site-Specific Monomethyl Auristatin E–based Antibody–Drug Conjugate for Treatment of Nectin-4–expressing Cancers
Authors: Zhou Wei , Fang Peng , Yu Dongan , Ren Hongyuan , You Meng , Yin Long , Mei Fei , Zhu Huikai , Wang Zhenzhen , Xu Hui , Cao Yuxia , Sun Xiaowei , Xu Xiaohong , Bi Jianjun , Wang Jin , Ma Lanping , Wang Xin , Chen Lin , Zhang Yongliang , Cen Xiaowei , Zhu Xi , Lou Liguang , Liu Datao , Tan Xiaoding , Yang Jinliang , Meng Tao , Shen Jingkang
Published: August 2023

Analytical results of 9MW2821 and enfortumab vedotin (EV)
Supplementary Table S4 from Preclinical Evaluation of 9MW2821, a Site-Specific Monomethyl Auristatin E–based Antibody–Drug Conjugate for Treatment of Nectin-4–expressing Cancers
Authors: Zhou Wei , Fang Peng , Yu Dongan , Ren Hongyuan , You Meng , Yin Long , Mei Fei , Zhu Huikai , Wang Zhenzhen , Xu Hui , Cao Yuxia , Sun Xiaowei , Xu Xiaohong , Bi Jianjun , Wang Jin , Ma Lanping , Wang Xin , Chen Lin , Zhang Yongliang , Cen Xiaowei , Zhu Xi , Lou Liguang , Liu Datao , Tan Xiaoding , Yang Jinliang , Meng Tao , Shen Jingkang
Published: August 2023

Patient information for breast cancer formalin-fixed paraffin-embedded samples
Supplementary Table S15 from Preclinical Evaluation of 9MW2821, a Site-Specific Monomethyl Auristatin E–based Antibody–Drug Conjugate for Treatment of Nectin-4–expressing Cancers
Authors: Zhou Wei , Fang Peng , Yu Dongan , Ren Hongyuan , You Meng , Yin Long , Mei Fei , Zhu Huikai , Wang Zhenzhen , Xu Hui , Cao Yuxia , Sun Xiaowei , Xu Xiaohong , Bi Jianjun , Wang Jin , Ma Lanping , Wang Xin , Chen Lin , Zhang Yongliang , Cen Xiaowei , Zhu Xi , Lou Liguang , Liu Datao , Tan Xiaoding , Yang Jinliang , Meng Tao , Shen Jingkang
Published: August 2023

Toxicity profiles of 9MW2821 in cynomolgus monkeys.
Supplementary Table S1 from Preclinical Evaluation of 9MW2821, a Site-Specific Monomethyl Auristatin E–based Antibody–Drug Conjugate for Treatment of Nectin-4–expressing Cancers
Authors: Zhou Wei , Fang Peng , Yu Dongan , Ren Hongyuan , You Meng , Yin Long , Mei Fei , Zhu Huikai , Wang Zhenzhen , Xu Hui , Cao Yuxia , Sun Xiaowei , Xu Xiaohong , Bi Jianjun , Wang Jin , Ma Lanping , Wang Xin , Chen Lin , Zhang Yongliang , Cen Xiaowei , Zhu Xi , Lou Liguang , Liu Datao , Tan Xiaoding , Yang Jinliang , Meng Tao , Shen Jingkang
Published: August 2023

Patient information for lung cancer formalin-fixed paraffin-embedded samples
Supplementary Fig.S10 from Preclinical Evaluation of 9MW2821, a Site-Specific Monomethyl Auristatin E–based Antibody–Drug Conjugate for Treatment of Nectin-4–expressing Cancers
Authors: Zhou Wei , Fang Peng , Yu Dongan , Ren Hongyuan , You Meng , Yin Long , Mei Fei , Zhu Huikai , Wang Zhenzhen , Xu Hui , Cao Yuxia , Sun Xiaowei , Xu Xiaohong , Bi Jianjun , Wang Jin , Ma Lanping , Wang Xin , Chen Lin , Zhang Yongliang , Cen Xiaowei , Zhu Xi , Lou Liguang , Liu Datao , Tan Xiaoding , Yang Jinliang , Meng Tao , Shen Jingkang
Published: August 2023

Mouse body weight from MDA-MB-468, NCI-H322 and HT1376 cell-derived xenograft studies.
Supplementary Fig.S1 from Preclinical Evaluation of 9MW2821, a Site-Specific Monomethyl Auristatin E–based Antibody–Drug Conjugate for Treatment of Nectin-4–expressing Cancers
Authors: Zhou Wei , Fang Peng , Yu Dongan , Ren Hongyuan , You Meng , Yin Long , Mei Fei , Zhu Huikai , Wang Zhenzhen , Xu Hui , Cao Yuxia , Sun Xiaowei , Xu Xiaohong , Bi Jianjun , Wang Jin , Ma Lanping , Wang Xin , Chen Lin , Zhang Yongliang , Cen Xiaowei , Zhu Xi , Lou Liguang , Liu Datao , Tan Xiaoding , Yang Jinliang , Meng Tao , Shen Jingkang
Published: August 2023

Structure of linker-payload complexes and conjugation process of 9MW2821.
Materials and Methods from Preclinical Evaluation of 9MW2821, a Site-Specific Monomethyl Auristatin E–based Antibody–Drug Conjugate for Treatment of Nectin-4–expressing Cancers
Authors: Zhou Wei , Fang Peng , Yu Dongan , Ren Hongyuan , You Meng , Yin Long , Mei Fei , Zhu Huikai , Wang Zhenzhen , Xu Hui , Cao Yuxia , Sun Xiaowei , Xu Xiaohong , Bi Jianjun , Wang Jin , Ma Lanping , Wang Xin , Chen Lin , Zhang Yongliang , Cen Xiaowei , Zhu Xi , Lou Liguang , Liu Datao , Tan Xiaoding , Yang Jinliang , Meng Tao , Shen Jingkang
Published: August 2023

Supplementary Materials and Methods
Supplementary tables from APR-246 Enhances Colorectal Cancer Sensitivity to Radiotherapy
Authors: Xie Xuqin , Fan Chuanwen , Luo Bin , Zhang Jing , Jensen Lasse D. , Burman Jonas , Jönsson Carolin , Ljusberg Anna , Larsson Peter , Zhao Zengren , Sun Xiao-Feng
Published: August 2023

Supplementary tables
Supplementary Figure Legends from APR-246 Enhances Colorectal Cancer Sensitivity to Radiotherapy
Authors: Xie Xuqin , Fan Chuanwen , Luo Bin , Zhang Jing , Jensen Lasse D. , Burman Jonas , Jönsson Carolin , Ljusberg Anna , Larsson Peter , Zhao Zengren , Sun Xiao-Feng
Published: August 2023

Supplementary Figure Legends
Supplementary Data from APR-246 Enhances Colorectal Cancer Sensitivity to Radiotherapy
Authors: Xie Xuqin , Fan Chuanwen , Luo Bin , Zhang Jing , Jensen Lasse D. , Burman Jonas , Jönsson Carolin , Ljusberg Anna , Larsson Peter , Zhao Zengren , Sun Xiao-Feng
Published: August 2023

p53Mut_log2FC of genes
Figure S9 from APR-246 Enhances Colorectal Cancer Sensitivity to Radiotherapy
Authors: Xie Xuqin , Fan Chuanwen , Luo Bin , Zhang Jing , Jensen Lasse D. , Burman Jonas , Jönsson Carolin , Ljusberg Anna , Larsson Peter , Zhao Zengren , Sun Xiao-Feng
Published: August 2023

Supplementary figure 9
Figure S8 from APR-246 Enhances Colorectal Cancer Sensitivity to Radiotherapy
Authors: Xie Xuqin , Fan Chuanwen , Luo Bin , Zhang Jing , Jensen Lasse D. , Burman Jonas , Jönsson Carolin , Ljusberg Anna , Larsson Peter , Zhao Zengren , Sun Xiao-Feng
Published: August 2023

Supplementary figure 8
Figure S7 from APR-246 Enhances Colorectal Cancer Sensitivity to Radiotherapy
Authors: Xie Xuqin , Fan Chuanwen , Luo Bin , Zhang Jing , Jensen Lasse D. , Burman Jonas , Jönsson Carolin , Ljusberg Anna , Larsson Peter , Zhao Zengren , Sun Xiao-Feng
Published: August 2023

Supplementary figure 7
Figure S6 from APR-246 Enhances Colorectal Cancer Sensitivity to Radiotherapy
Authors: Xie Xuqin , Fan Chuanwen , Luo Bin , Zhang Jing , Jensen Lasse D. , Burman Jonas , Jönsson Carolin , Ljusberg Anna , Larsson Peter , Zhao Zengren , Sun Xiao-Feng
Published: August 2023

Supplementary figure 6
Figure S4 from APR-246 Enhances Colorectal Cancer Sensitivity to Radiotherapy
Authors: Xie Xuqin , Fan Chuanwen , Luo Bin , Zhang Jing , Jensen Lasse D. , Burman Jonas , Jönsson Carolin , Ljusberg Anna , Larsson Peter , Zhao Zengren , Sun Xiao-Feng
Published: August 2023

Supplementary figure 4
Figure S10 from APR-246 Enhances Colorectal Cancer Sensitivity to Radiotherapy
Authors: Xie Xuqin , Fan Chuanwen , Luo Bin , Zhang Jing , Jensen Lasse D. , Burman Jonas , Jönsson Carolin , Ljusberg Anna , Larsson Peter , Zhao Zengren , Sun Xiao-Feng
Published: August 2023

Supplementary figure 10
Data from Vincristine Enhances the Efficacy of MEK Inhibitors in Preclinical Models of KRAS-mutant Colorectal Cancer
Authors: Ghosh Susmita , Fan Fan , Powell Reid T. , Roszik Jason , Park Yong Sung , Stephan Clifford , Sebastian Manu , Tan Lin , Sorokin Alexey V. , Lorenzi Philip L. , Kopetz Scott , Ellis Lee M. , Bhattacharya Rajat
Published: August 2023

Abstract
Mutations in KRAS are found in more than 50% of tumors from patients with metastatic colorectal cancer (mCRC). However, direct targeting of most KRAS mutations is difficult; even the recently developed KRASG12C inhibitors failed to show significant benefit in patients with mCRC. Single agents targeting mitogen-activated protein kinase kinase (MEK), a downstream mediator of RAS, have also been ineffective in colorectal cancer. To identify drugs that can enhance the efficacy of MEK inhibitors, we performed unbiased high-throughput screening using colorectal cancer spheroids. We used trametinib as the anchor drug and examined combinations of trametinib with the NCI-approved Oncology Library version 5. The initial screen, and following focused validation screens, identified vincristine as being strongly synergistic with trametinib. In vitro, the combination strongly inhibited cell growth, reduced clonogenic survival, and enhanced apoptosis compared with monotherapies in multiple KRAS-mutant colorectal cancer cell lines. Furthermore, this combination significantly inhibited tumor growth, reduced cell proliferation, and increased apoptosis in multiple KRAS-mutant patient-derived xenograft mouse models. In vivo studies using drug doses that reflect clinically achievable doses demonstrated that the combination was well tolerated by mice. We further determined that the mechanism underlying the synergistic effect of the combination was due to enhanced intracellular accumulation of vincristine associated with MEK inhibition. The combination also significantly decreased p-mTOR levels in vitro, indicating that it inhibits both RAS-RAF-MEK and PI3K-AKT-mTOR survival pathways. Our data thus provide strong evidence that the combination of trametinib and vincristine represents a novel therapeutic option to be studied in clinical trials for patients with KRAS-mutant mCRC.
Significance:
Our unbiased preclinical studies have identified vincristine as an effective combination partner for the MEK inhibitor trametinib and provide a novel therapeutic option to be studied in patients with KRAS-mutant colorectal cancer.
Data from Preclinical Evaluation of 9MW2821, a Site-Specific Monomethyl Auristatin E–based Antibody–Drug Conjugate for Treatment of Nectin-4–expressing Cancers
Authors: Zhou Wei , Fang Peng , Yu Dongan , Ren Hongyuan , You Meng , Yin Long , Mei Fei , Zhu Huikai , Wang Zhenzhen , Xu Hui , Cao Yuxia , Sun Xiaowei , Xu Xiaohong , Bi Jianjun , Wang Jin , Ma Lanping , Wang Xin , Chen Lin , Zhang Yongliang , Cen Xiaowei , Zhu Xi , Lou Liguang , Liu Datao , Tan Xiaoding , Yang Jinliang , Meng Tao , Shen Jingkang
Published: August 2023

Abstract
Overexpression of nectin cell adhesion protein 4 correlates with cancer progression and poor prognosis in many human malignancies. Enfortumab vedotin (EV) is the first nectin-4–targeting antibody–drug conjugate (ADC) approved by the FDA for the treatment of urothelial cancer. However, inadequate efficacy has limited progress in the treatment of other solid tumors with EV. Furthermore, ocular, pulmonary, and hematologic toxic side effects are common in nectin-4–targeted therapy, which frequently results in dose reduction and/or treatment termination. Thus, we designed a second generation nectin-4–specific drug, 9MW2821, based on interchain-disulfide drug conjugate technology. This novel drug contained a site specifically conjugated humanized antibody and the cytotoxic moiety monomethyl auristatin E. The homogenous drug–antibody ratio and novel linker chemistry of 9MW2821 increased the stability of conjugate in the systemic circulation, enabling highly efficient drug delivery and avoiding off-target toxicity. In preclinical evaluation, 9MW2821 exhibited nectin-4–specific cell binding, efficient internalization, bystander killing, and equivalent or superior antitumor activity compared with EV in both cell line–derived xenograft and patient-derived xenograft (PDX) models. In addition, 9MW2821 demonstrated a favorable safety profile; the highest nonseverely toxic dose in monkey toxicologic studies was 6 mg/kg, with milder adverse events compared with EV. Overall, 9MW2821 is a nectin-4–directed, investigational ADC based on innovative technology that endowed the drug with compelling preclinical antitumor activity and a favorable therapeutic index. The 9MW2821 ADC is being investigated in a phase I/II clinical trial (NCT05216965 and NCT05773937) in patients with advanced solid tumors.
Data from APR-246 Enhances Colorectal Cancer Sensitivity to Radiotherapy
Authors: Xie Xuqin , Fan Chuanwen , Luo Bin , Zhang Jing , Jensen Lasse D. , Burman Jonas , Jönsson Carolin , Ljusberg Anna , Larsson Peter , Zhao Zengren , Sun Xiao-Feng
Published: August 2023

Abstract
p53 mutation is common and highly related to radiotherapy resistance in rectal cancer. APR-246, as a small molecule, can restore the tumor-suppressor function to mutant p53. As there is currently no existing study on combining APR-246 with radiation in rectal cancer, our objective was to investigate whether APR-246 could enhance the sensitivity of colorectal cancer cells, regardless of their p53 status, to radiation treatment. The combination treatment had synergistic effects on HCT116p53-R248W/− (p53Mut) cells, followed by HCT116p53+/+ [wild-type p53 (p53WT)] cells, and exhibited an additive effect on HCT116p53−/− (p53Null) cells through inhibiting proliferation, enhancing reactive oxygen species, and apoptosis. The results were confirmed in zebrafish xenografts. Mechanistically, p53Mut and p53WT cells shared more activated pathways and differentially expressed genes following the combination treatment, compared with p53Null cells, although the combination treatment regulated individual pathways in the different cell lines. APR-246 mediated radiosensitization effects through p53-dependent and -independent ways. The results may provide evidence for a clinical trial of the combination in patients with rectal cancer.
Figure S7 from Dynamic Intestinal Stem Cell Plasticity and Lineage Remodeling by a Nutritional Environment Relevant to Human Risk for Tumorigenesis
Authors: Choi Jiahn , Zhang Xusheng , Li Wenge , Houston Michele , Peregrina Karina , Dubin Robert , Ye Kenny , Augenlicht Leonard
Published: August 2023

The western diet causes chronic pro-tumorigenic inflammation.
Figure S5 from Dynamic Intestinal Stem Cell Plasticity and Lineage Remodeling by a Nutritional Environment Relevant to Human Risk for Tumorigenesis
Authors: Choi Jiahn , Zhang Xusheng , Li Wenge , Houston Michele , Peregrina Karina , Dubin Robert , Ye Kenny , Augenlicht Leonard
Published: August 2023

Single cell RNAsequencing following 4 days of dietary switch, or then switch back and comparison to pathways altered in stem cells by Ppargc1a genetic inactivation.
Figure S3 from Dynamic Intestinal Stem Cell Plasticity and Lineage Remodeling by a Nutritional Environment Relevant to Human Risk for Tumorigenesis
Authors: Choi Jiahn , Zhang Xusheng , Li Wenge , Houston Michele , Peregrina Karina , Dubin Robert , Ye Kenny , Augenlicht Leonard
Published: August 2023

The western diet suppresses expression of a large number of genes encoding subunits of each of the 5 complexes of mitochondrial electron transport.
Figure S2 from Dynamic Intestinal Stem Cell Plasticity and Lineage Remodeling by a Nutritional Environment Relevant to Human Risk for Tumorigenesis
Authors: Choi Jiahn , Zhang Xusheng , Li Wenge , Houston Michele , Peregrina Karina , Dubin Robert , Ye Kenny , Augenlicht Leonard
Published: August 2023

The western diet elevates and suppresses multiple pathways by 3 months, most persisting to 12 months, and reversible by switching to control diet.
Figure S1 from Dynamic Intestinal Stem Cell Plasticity and Lineage Remodeling by a Nutritional Environment Relevant to Human Risk for Tumorigenesis
Authors: Choi Jiahn , Zhang Xusheng , Li Wenge , Houston Michele , Peregrina Karina , Dubin Robert , Ye Kenny , Augenlicht Leonard
Published: August 2023

The western diet extensively reprograms Lgr5hi stem cells that expands with time and is reversible. This includes the TCA cycle and Oxphos pathways
Supplementary Table 5 from ZEB1 Is Regulated by K811 Acetylation to Promote Stability, NuRD Complex Interactions, EMT, and NSCLC Metastasis
Authors: Perez-Oquendo Mabel , Manshouri Roxsan , Tian Yanhua , Fradette Jared J. , Rodriguez B. Leticia , Kundu Samrat T. , Gibbons Don L.
Published: August 2023

ChIP Primer Sequences