bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Resolving the Heterogeneous Tumor-Centric Cellular Neighborhood through Multiplexed, Spatial Paracrine Interactions in the Setting of Immune Checkpoint Blockade
Authors: Maus Rachel L.G. , Leontovich Alexey A. , Moore Raymond M. , Becher Laura , Nevala Wendy K. , Flotte Thomas J. , Guo Ruifeng , Schimke Jill M. , Dicke Betty A. , Yan Yiyi , Markovic Svetomir N.
Published: April 2023

Direct interactions between tumor and immune cells mediate the antitumor effect of all modern cancer immunotherapeutic agents. Simultaneously, tumor cells have evolved mechanisms of evasion, including the downregulation of HLA-I, potentially disrupting the mechanism of action employed by many immune checkpoint inhibitors. And yet, the in situ interplay between these cells within the tumor immune microenvironment (TIME) remains elusive. Recent advances in histologic multiplex bioimaging platforms have enabled in-depth molecular characterization of single cells within spatially preserved and clinically archived tumor tissues. Herein, we applied multiplex immunofluorescence to excisional lymph node biopsies from 14 patients with metastatic melanoma who experienced clear objective responses to immunotherapy (7 complete response; 7 progressive disease) to determine distinguishing features of the TIME in the pretreatment setting. Distinct regions of the TIME were evaluated using 35 proteins probing tumor, immune, and vasculature components across 323 fields of view. Single-cell compositional analysis confirmed established prognostic immune cell types including increased prevalence of cytotoxic T cells within the tumor core fields of view of responders. Integrating single-cell quantification with the spatial arrangement of cellular neighborhoods surrounding tumor cells revealed novel, spatial immune signatures capable of stratifying TIME based on clinical response. Our analysis revealed dynamic cellular composition of the tumor-centric cellular neighborhood (TCCN) based on anatomic subregion, functional expression of HLA-I by the index tumor cell and ultimately clinical response to immunotherapy. Overall, this study provides an analytic framework to resolve the cellular complexity of the TIME, increasingly relevant to the outcomes of modern cancer immunotherapy.
Significance:
Findings from this work propose a novel approach to resolving clinical heterogeneity of the TIME by objectively quantifying the cellular interactions occurring in metastatic melanoma lymph node tissue utilizing multiplex immunofluorescence. This study provides an analytic and biologically derived unit of measure, the TCCN which is customizable for studying critical paracrine interactions within spatially preserved tissue of various cancers and across the spectrum of multiplex imaging modalities.
Data from MYCMI-7: A Small MYC-Binding Compound that Inhibits MYC: MAX Interaction and Tumor Growth in a MYC-Dependent Manner
Authors: Castell Alina , Yan Qinzi , Fawkner Karin , Bazzar Wesam , Zhang Fan , Wickström Malin , Alzrigat Mohammad , Franco Marcela , Krona Cecilia , Cameron Donald P. , Dyberg Cecilia , Olsen Thale Kristin , Verschut Vasiliki , Schmidt Linnéa , Lim Sheryl Y. , Mahmoud Loay , Hydbring Per , Lehmann Sören , Baranello Laura , Nelander Sven , Johnsen John Inge , Larsson Lars-Gunnar
Published: April 2023

Deregulated expression of MYC family oncogenes occurs frequently in human cancer and is often associated with aggressive disease and poor prognosis. While MYC is a highly warranted target, it has been considered “undruggable,” and no specific anti-MYC drugs are available in the clinic. We recently identified molecules named MYCMIs that inhibit the interaction between MYC and its essential partner MAX. Here we show that one of these molecules, MYCMI-7, efficiently and selectively inhibits MYC:MAX and MYCN:MAX interactions in cells, binds directly to recombinant MYC, and reduces MYC-driven transcription. In addition, MYCMI-7 induces degradation of MYC and MYCN proteins. MYCMI-7 potently induces growth arrest/apoptosis in tumor cells in a MYC/MYCN-dependent manner and downregulates the MYC pathway on a global level as determined by RNA sequencing. Sensitivity to MYCMI-7 correlates with MYC expression in a panel of 60 tumor cell lines and MYCMI-7 shows high efficacy toward a collection of patient-derived primary glioblastoma and acute myeloid leukemia (AML) ex vivo cultures. Importantly, a variety of normal cells become G1 arrested without signs of apoptosis upon MYCMI-7 treatment. Finally, in mouse tumor models of MYC-driven AML, breast cancer, and MYCN-amplified neuroblastoma, treatment with MYCMI-7 downregulates MYC/MYCN, inhibits tumor growth, and prolongs survival through apoptosis with few side effects. In conclusion, MYCMI-7 is a potent and selective MYC inhibitor that is highly relevant for the development into clinically useful drugs for the treatment of MYC-driven cancer.
Significance:
Our findings demonstrate that the small-molecule MYCMI-7 binds MYC and inhibits interaction between MYC and MAX, thereby hampering MYC-driven tumor cell growth in culture and in vivo while sparing normal cells.
Data from Peripheral Blood Monocyte Abundance Predicts Outcomes in Patients with Breast Cancer
Authors: Axelrod Margaret L. , Wang Yu , Xu Yaomin , Sun Xiaopeng , Bejan Cosmin A. , Gonzalez-Ericsson Paula I. , Nunnery Sara , Bergman Riley E. , Donaldson Joshua , Guerrero-Zotano Angel L. , Massa Chiara , Seliger Barbara , Sanders Melinda , Mayer Ingrid A. , Balko Justin M.
Published: April 2023

Biomarkers of response are needed in breast cancer to stratify patients to appropriate therapies and avoid unnecessary toxicity. We used peripheral blood gene expression and cell-type abundance to identify biomarkers of response and recurrence in neoadjuvant chemotherapy–treated patients with breast cancer. We identified a signature of IFN and complement response that was higher in the blood of patients with pathologic complete response. This signature was preferentially expressed by monocytes in single-cell RNA sequencing. Monocytes are routinely measured clinically, enabling examination of clinically measured monocytes in multiple independent cohorts. We found that peripheral monocytes were higher in patients with good outcomes in four cohorts of patients with breast cancer. Blood gene expression and cell type abundance biomarkers may be useful for prognostication in breast cancer.
Significance:
Biomarkers are needed in breast cancer to identify patients at risk for recurrence. Blood is an attractive site for biomarker identification due to the relative ease of longitudinal sampling. Our study suggests that blood-based gene expression and cell-type abundance biomarkers may have clinical utility in breast cancer.
Data from Type-I Interferon Signaling Is Essential for Robust Metronomic Chemo-Immunogenic Tumor Regression in Murine Breast Cancer
Authors: Vergato Cameron , Doshi Kshama A. , Roblyer Darren , Waxman David J.
Published: April 2023

Many patients with breast cancer have a poor prognosis with limited therapeutic options. Here, we investigated the potential of chemo-immunogenic therapy as an avenue of treatment. We utilized two syngeneic mouse mammary tumor models, 4T1 and E0771, to examine the chemo-immunogenic potential of cyclophosphamide and the mechanistic contributions of cyclophosphamide-activated type-I IFN signaling to therapeutic activity. Chemically activated cyclophosphamide induced robust IFNα/β receptor-1–dependent signaling linked to hundreds of IFN-stimulated gene responses in both cell lines. Furthermore, in 4T1 tumors, cyclophosphamide given on a medium-dose, 6-day intermittent metronomic schedule induced strong IFN signaling but comparatively weak immune cell infiltration associated with long-term tumor growth stasis. Induction of IFN signaling was somewhat weaker in E0771 tumors but was followed by widespread downstream gene responses, robust immune cell infiltration, and extensive, prolonged tumor regression. The immune dependence of these effective antitumor responses was established by CD8 T-cell immunodepletion, which blocked cyclophosphamide-induced E0771 tumor regression and led to tumor stasis followed by regrowth. Strikingly, IFNα/β receptor-1 antibody blockade was even more effective in preventing E0771 immune cell infiltration and blocked the major tumor regression induced by cyclophosphamide treatment. Type-I IFN signaling is thus essential for the robust chemo-immunogenic response of these tumors to cyclophosphamide administered on a metronomic schedule.
Significance:
Many patients with breast cancer have few therapeutic options. We show that cyclophosphamide treatment induces extensive tumor regression in a syngeneic mouse model of breast cancer via a chemo-immunogenic mechanism linked to type-I IFN production. Our findings establish that IFN signaling is essential for the robust antitumor actions of cyclophosphamide and suggest that treatment resistance may stem from silencing the IFN pathway. This suggests a new avenue for improving breast cancer treatment efficacy.
Data from Stromal FAP Expression is Associated with MRI Visibility and Patient Survival in Prostate Cancer
Authors: Pellinen Teijo , Sandeman Kevin , Blom Sami , Turkki Riku , Hemmes Annabrita , Välimäki Katja , Eineluoto Juho , Kenttämies Anu , Nordling Stig , Kallioniemi Olli , Rannikko Antti , Mirtti Tuomas
Published: April 2023

Some clinically significant prostate cancers are missed by MRI. We asked whether the tumor stroma in surgically treated localized prostate cancer lesions positive or negative with MRI are different in their cellular and molecular properties, and whether the differences are reflected to the clinical course of the disease.

We profiled the stromal and immune cell composition of MRI-classified tumor lesions by applying multiplexed fluorescence IHC (mfIHC) and automated image analysis in a clinical cohort of 343 patients (cohort I). We compared stromal variables between MRI-visible lesions, invisible lesions, and benign tissue and assessed the predictive significance for biochemical recurrence (BCR) and disease-specific survival (DSS) using Cox regression and log-rank analysis. Subsequently, we carried out a prognostic validation of the identified biomarkers in a population-based cohort of 319 patients (cohort II).

MRI true-positive lesions are different from benign tissue and MRI false-negative lesions in their stromal composition. CD163+ cells (macrophages) and fibroblast activation protein (FAP)+ cells were more abundant in MRI true-positive than in MRI false-negative lesions or benign areas. In MRI true-visible lesions, a high proportion of stromal FAP+ cells was associated with PTEN status and increased immune infiltration (CD8+, CD163+), and predicted elevated risk for BCR. High FAP phenotype was confirmed to be a strong indicator of poor prognosis in two independent patient cohorts using also conventional IHC.

The molecular composition of the tumor stroma may determine whether early prostate lesions are detectable by MRI and associates with survival after surgical treatment.
Significance:
These findings may have a significant impact on clinical decision making as more radical treatments may be recommended for men with a combination of MRI-visible primary tumors and FAP+ tumor stroma.
Data from Redirecting T-cell Activity with Anti-BCMA/Anti-CD3 Bispecific Antibodies in Chronic Lymphocytic Leukemia and Other B-cell Lymphomas
Authors: Martens Anne W.J. , Rietveld Joanne M. , de Boer Renate , Peters Fleur S. , Ngo An , van Mil Lotte W.H.G. , de Heer Koen , Spaargaren Marcel , Verkleij Christie P.M. , van de Donk Niels W.C.J. , Adams Homer C. , Eldering Eric , van Noesel Carel J.M. , Verona Raluca , Kater Arnon P.
Published: April 2023

T-cell redirecting bispecific antibodies hold high promise for treatment of B-cell malignancies. B-cell maturation antigen (BCMA) exhibits high expression on normal and malignant mature B cells including plasma cells, which can be enhanced by inhibition of γ-secretase. BCMA is considered a validated target in multiple myeloma but whether mature B-cell lymphomas can be targeted by the BCMAxCD3 T-cell redirector teclistamab is currently unknown. BCMA expression on B-cell non–Hodgkin lymphoma and primary chronic lymphocytic leukemia (CLL) cells was assessed by flow cytometry and/or IHC. To assess teclistamab efficacy, cells were treated with teclistamab in presence of effector cells with/without γ-secretase inhibition. BCMA could be detected on all tested mature B-cell malignancy cell lines, while expression levels varied per tumor type. γ-secretase inhibition universally increased BCMA surface expression. These data were corroborated in primary samples from patients with Waldenstrom's macroglobulinemia, CLL, and diffuse large B-cell lymphoma. Functional studies with the B-cell lymphoma cell lines revealed teclistamab-mediated T-cell activation, proliferation, and cytotoxicity. This was independent of the level of BCMA expression, but generally lower in mature B-cell malignancies compared with multiple myeloma. Despite low BCMA levels, healthy donor T cells and CLL-derived T cells induced lysis of (autologous) CLL cells upon addition of teclistamab. These data show that BCMA is expressed on various B-cell malignancies and that lymphoma cell lines and primary CLL can be targeted using teclistamab. Further studies to understand the determinants of response to teclistamab are required to identify which other diseases might be suitable for teclistamab targeting.
Significance:
Besides reported BCMA expression on multiple myeloma, we demonstrate BCMA can be detected and enhanced using γ-secretase inhibition on cell lines and primary material of various B-cell malignancies. Furthermore, using CLL we demonstrate that low BCMA-expressing tumors can be targeted efficiently using the BCMAxCD3 DuoBody teclistamab.
Data from Serum Carotenoids and Cancer-Related Fatigue: An Analysis of the 2005–2006 National Health and Nutrition Examination Survey
Authors: Kleckner Amber S. , van Wijngaarden Edwin , Jusko Todd A. , Kleckner Ian R. , Lin Po-Ju , Mustian Karen M. , Peppone Luke J.
Published: April 2023

Cancer-related fatigue is a prevalent, debilitating condition, and preliminary evidence suggests a relationship between higher diet quality and lower fatigue. Serum-based carotenoids, Vitamin A, and Vitamin E are biomarkers of fruit and vegetable intake and therefore diet quality. To further elucidate the link between diet quality and cancer-related fatigue, associations were assessed between these serum-based nutrients and fatigue among American adults with special attention to cancer history. Data were analyzed from the United States 2005–2006 National Health and Nutrition Examination Survey dataset. Ten carotenoids, vitamin A, vitamin E, and γ-tocopherol were measured from fasting blood samples and fatigue was patient-reported. Associations between carotenoid concentration and fatigue were estimated using ordinal logistic regression models. Adjusted models included a diagnosis of cancer (with the exception on nonmelanoma skin cancer, yes/no), age, body mass index, race/ethnicity, education, and exercise habits as covariates, and additional models included a cancer × nutrient interaction. Of 4,091 participants, 272 (8.0%) reported a history of cancer. Greater fatigue was associated with lower serum trans-lycopene, retinyl palmitate, and retinyl stearate (all P < 0.05) in separate models adjusting for potential confounders. For these nutrients, a one-SD increase in nutrient was associated with a 6.8%–9.9% lower risk of greater fatigue. Among cancer survivors only (n = 272), statistically significant associations were not observed between any of the nutrients and fatigue. In conclusion, greater serum concentrations of carotenoid biomarkers were associated with less fatigue. These results support further exploration into relationships between carotenoid intake, diet quality, and persistent fatigue.
Significance:
Cancer-related fatigue often persists for years into survivorship, reduces quality of life, and prevents people from returning to their lives before cancer. Interventions to address cancer-related fatigue are much needed. Herein, serum carotenoids were associated with lower fatigue, thereby supporting further development of nutritional interventions to address fatigue in survivorship.
Data from Depletion of Mannose Receptor–Positive Tumor-associated Macrophages via a Peptide-targeted Star-shaped Polyglutamate Inhibits Breast Cancer Progression in Mice
Authors: Lepland Anni , Malfanti Alessio , Haljasorg Uku , Asciutto Eliana K. , Pickholz Monica , Bringas Mauro , Đorđević Snežana , Salumäe Liis , Peterson Pärt , Teesalu Tambet , Vicent María J. , Scodeller Pablo
Published: April 2023

Although many studies have explored the depletion of tumor-associated macrophages (TAM) as a therapeutic strategy for solid tumors, currently available compounds suffer from poor efficacy and dose-limiting side effects. Here, we developed a novel TAM-depleting agent (“OximUNO”) that specifically targets CD206+ TAMs and demonstrated efficacy in a triple-negative breast cancer (TNBC) mouse model. OximUNO comprises a star-shaped polyglutamate (St-PGA) decorated with the CD206-targeting peptide mUNO that carries the chemotherapeutic drug doxorubicin (DOX). In the TNBC model, a fluorescently labeled mUNO-decorated St-PGA homed to CD206+ TAMs within primary lesions and metastases. OximUNO exhibited no acute liver or kidney toxicity in vivo. Treatment with OximUNO reduced the progression of primary tumor lesions and pulmonary metastases, significantly diminished the number of CD206+ TAMs and increased the CD8/FOXP3 expression ratio (indicating immunomodulation). Our findings suggest the potential benefit of OximUNO as a TAM-depleting agent for TNBC treatment. Importantly, our studies also represent a novel design of a peptide-targeted St-PGA as a targeted therapeutic nanoconjugate.
Significance:
A peptide-targeted nanoformulation of DOX exclusively eliminates mannose receptor+ TAMs in breast cancer models, generating response without off-target effects (a drawback of many TAM-depleting agents under clinical study).
Data from BRCA1-Associated RING Domain-1 (BARD1) Loss and GBP1 Expression Enhance Sensitivity to DNA Damage in Ewing Sarcoma
Authors: Maurer Lisa M. , Daley Jessica D. , Mukherjee Elina , Venier Rosemarie E. , Julian Claire M. , Bailey Nathanael G. , Jacobs Michelle F. , Kumar-Sinha Chandan , Raphael Haley , Periyapatna Nivitha , Weiss Kurt , Janeway Katherine A. , Mody Rajen , Lucas Peter C. , McAllister-Lucas Linda M. , Bailey Kelly M.
Published: April 2023

Ewing sarcoma is a fusion oncoprotein–driven primary bone tumor. A subset of patients (∼10%) with Ewing sarcoma are known to harbor germline variants in a growing number of genes involved in DNA damage repair. We recently reported our discovery of a germline mutation in the DNA damage repair protein BARD1 (BRCA1-associated RING domain-1) in a patient with Ewing sarcoma. BARD1 is recruited to the site of DNA double stranded breaks via the PARP protein and plays a critical role in DNA damage response pathways including homologous recombination. We thus questioned the impact of BARD1 loss on Ewing cell sensitivity to DNA damage and the Ewing sarcoma transcriptome. We demonstrate that PSaRC318 cells, a novel patient-derived cell line harboring a pathogenic BARD1 variant, are sensitive to PARP inhibition and by testing the effect of BARD1 depletion in additional Ewing sarcoma cell lines, we confirm that BARD1 loss enhances cell sensitivity to PARP inhibition plus radiation. In addition, RNA-sequencing analysis revealed that loss of BARD1 results in the upregulation of GBP1 (guanylate-binding protein 1), a protein whose expression is associated with variable response to therapy depending on the adult carcinoma subtype examined. Here, we demonstrate that GBP1 contributes to the enhanced sensitivity of BARD1-deficient Ewing cells to DNA damage. Together, our findings demonstrate the impact of loss-of function mutations in DNA damage repair genes, such as BARD1, on Ewing sarcoma treatment response.
Significance:
This work provides preclinical support for the inclusion of pediatric patients with advanced Ewing sarcoma and pathogenic germline variants in BARD1 in future clinical trials testing novel agents inducing DNA damage/targeting DNA damage repair.
Data from Uterine Lavage Identifies Cancer Mutations and Increased TP53 Somatic Mutation Burden in Individuals with Ovarian Cancer
Authors: Ghezelayagh Talayeh S. , Kohrn Brendan F. , Fredrickson Jeanne , Manhardt Enna , Radke Marc R. , Katz Ronit , Gray Heidi J. , Urban Renata R. , Pennington Kathryn P. , Liao John B. , Doll Kemi M. , Simons Elise J. , Burzawa Jennifer K. , Goff Barbara A. , Speiser Paul , Swisher Elizabeth M. , Norquist Barbara M. , Risques Rosa Ana
Published: April 2023

Current screening methods for ovarian cancer have failed to demonstrate a significant reduction in mortality. Uterine lavage combined with TP53 ultradeep sequencing for the detection of disseminated ovarian cancer cells has emerged as a promising tool, but this approach has not been tested for early-stage disease or non-serous histologies. In addition, lavages carry multiple background mutations, the significance of which is poorly understood. Uterine lavage was collected preoperatively in 34 patients undergoing surgery for suspected ovarian malignancy including 14 patients with benign disease and 20 patients with ovarian cancer [6 non-serous and 14 high-grade serous-like (serous)]. Ultradeep duplex sequencing (∼3,000×) with a panel of common ovarian cancer genes identified the tumor mutation in 33% of non-serous (all early stage) and 79% of serous cancers (including four early stage). In addition, all lavages carried multiple somatic mutations (average of 25 mutations per lavage), more than half of which corresponded to common cancer driver mutations. Driver mutations in KRAS, PIK3CA, PTEN, PPP2R1A, and ARID1A presented as larger clones than non-driver mutations and with similar frequency in lavages from patients with and without ovarian cancer, indicating prevalent somatic evolution in all patients. Driver TP53 mutations, however, presented as significantly larger clones and with higher frequency in lavages from individuals with ovarian cancer, suggesting that TP53-specific clonal expansions are linked to ovarian cancer development. Our results demonstrate that lavages capture cancer cells, even from early-stage cancers, as well as other clonal expansions and support further exploration of TP53 mutation burden as a potential ovarian cancer risk factor.
Significance:
Cancer driver mutations are found in uterine lavage DNA in all individuals, but driver TP53 mutations presented as significantly larger clones and with higher frequency in lavages from individuals with ovarian cancer. This suggests that TP53-specific clonal expansion plays a role in tumorigenesis and presents opportunities for early detection.
Data from Dietary Nonstarch Polysaccharide Intake and Risk of Colorectal Cancer: Findings from the Singapore Chinese Health Study
Authors: Yu Yi-Chuan , Paragomi Pedram , Jin Aizhen , Wang Renwei , Schoen Robert E. , Koh Woon-Puay , Yuan Jian-Min , Luu Hung N.
Published: April 2023

Dietary fiber or nonstarch polysaccharides (NSP) may provide protection from colorectal cancer development. Epidemiologic studies on the association between dietary fiber and colorectal cancer is inconsistent are limited on NSP as a modifiable risk factor. Using the Singapore Chinese Health Study, a population-based prospective cohort of 61,321 cancer-free middle-aged or older Chinese Singaporeans, we examined the association between dietary fiber and NSP intakes and colorectal cancer risk. Fiber and NSP intakes at baseline were obtained using a validated semiquantitative food frequency questionnaire coupled with the Singapore Food Composition Database. Cox proportional hazard regression model was used to estimate the HRs and respective 95% confidence intervals (CI) for colorectal cancer associated with dietary fiber and NSP intakes after adjusting for potential confounders. After an average of 17.5 years of follow-up, 2,140 participants developed colorectal cancer. NSP was inversely associated with the risk of colorectal cancer in a dose-dependent manner, whereas dietary fiber was not associated with risk of colorectal cancer overall or histologic subtypes. The multivariable-adjusted HRs (95% CIs) of colorectal cancer for quartiles 2, 3, and 4 of dietary NSP intake were 0.99 (0.88–1.11), 0.98 (0.87–1.11), and 0.84 (0.73–0.95), respectively, compared with the lowest quartile (Ptrend = 0.006). This inverse association was more apparent for colon cancer (HRQ4 vs. Q1 = 0.79, 95% CI: 0.67–0.93, Ptrend = 0.003) than rectal cancer (HR Q4 vs. Q1 = 0.92, 95% CI: 0.74–1.13, Ptrend = 0.53). Our findings suggested that dietary NSP but not fiber is associated with a reduced risk of colon cancer in Chinese Singaporeans.
Significance:
NSPs may be beneficial for colorectal cancer primary prevention.
Data from A Spatially Resolved Mechanistic Growth Law for Cancer Drug Development Predicting Tumor Growing Fractions
Authors: Nasim Adam , Yates James , Derks Gianne , Dunlop Carina
Published: April 2023

Mathematical models used in preclinical drug discovery tend to be empirical growth laws. Such models are well suited to fitting the data available, mostly longitudinal studies of tumor volume; however, they typically have little connection with the underlying physiologic processes. This lack of a mechanistic underpinning restricts their flexibility and potentially inhibits their translation across studies including from animal to human. Here we present a mathematical model describing tumor growth for the evaluation of single-agent cytotoxic compounds that is based on mechanistic principles. The model can predict spatial distributions of cell subpopulations and account for spatial drug distribution effects within tumors. Importantly, we demonstrate that the model can be reduced to a growth law similar in form to the ones currently implemented in pharmaceutical drug development for preclinical trials so that it can integrated into the current workflow. We validate this approach for both cell-derived xenograft and patient-derived xenograft (PDX) data. This shows that our theoretical model fits as well as the best performing and most widely used models. However, in addition, the model is also able to accurately predict the observed growing fraction of tumours. Our work opens up current preclinical modeling studies to also incorporating spatially resolved and multimodal data without significant added complexity and creates the opportunity to improve translation and tumor response predictions.
Significance:
This theoretical model has the same mathematical structure as that currently used for drug development. However, its mechanistic basis enables prediction of growing fraction and spatial variations in drug distribution.
Data from A Preclinical and Phase Ib Study of Palbociclib plus Nab-Paclitaxel in Patients with Metastatic Adenocarcinoma of the Pancreas
Authors: Hidalgo Manuel , Garcia-Carbonero Rocio , Lim Kian-Huat , Messersmith Wells A. , Garrido-Laguna Ignacio , Borazanci Erkut , Lowy Andrew M. , Medina Rodriguez Laura , Laheru Daniel , Salvador-Barbero Beatriz , Malumbres Marcos , Shields David J. , Grossman Joseph E. , Huang Xin , Tammaro Meggan , Martini Jean-François , Yu Yanke , Kern Kenneth , Macarulla Teresa
Published: April 2023

Purpose:
To assess the preclinical efficacy, clinical safety and efficacy, and MTD of palbociclib plus nab-paclitaxel in patients with advanced pancreatic ductal adenocarcinoma (PDAC).
Experimental Design:
Preclinical activity was tested in patient-derived xenograft (PDX) models of PDAC. In the open-label, phase I clinical study, the dose-escalation cohort received oral palbociclib initially at 75 mg/day (range, 50‒125 mg/day; modified 3+3 design; 3/1 schedule); intravenous nab-paclitaxel was administered weekly for 3 weeks/28-day cycle at 100‒125 mg/m2. The modified dose–regimen cohorts received palbociclib 75 mg/day (3/1 schedule or continuously) plus nab-paclitaxel (biweekly 125 or 100 mg/m2, respectively). The prespecified efficacy threshold was 12-month survival probability of ≥65% at the MTD.
Results:
Palbociclib plus nab-paclitaxel was more effective than gemcitabine plus nab-paclitaxel in three of four PDX models tested; the combination was not inferior to paclitaxel plus gemcitabine. In the clinical trial, 76 patients (80% received prior treatment for advanced disease) were enrolled. Four dose-limiting toxicities were observed [mucositis (n = 1), neutropenia (n = 2), febrile neutropenia (n = 1)]. The MTD was palbociclib 100 mg for 21 of every 28 days and nab-paclitaxel 125 mg/m2 weekly for 3 weeks in a 28-day cycle. Among all patients, the most common all-causality any-grade adverse events were neutropenia (76.3%), asthenia/fatigue (52.6%), nausea (42.1%), and anemia (40.8%). At the MTD (n = 27), the 12-month survival probability was 50% (95% confidence interval, 29.9–67.2).
Conclusions:
This study showed the tolerability and antitumor activity of palbociclib plus nab-paclitaxel treatment in patients with PDAC; however, the prespecified efficacy threshold was not met.
Trial Registration:
Pfizer Inc (NCT02501902)
Significance:
In this article, the combination of palbociclib, a CDK4/6 inhibitor, and nab-paclitaxel in advanced pancreatic cancer evaluates an important drug combination using translational science. In addition, the work presented combines preclinical and clinical data along with pharmacokinetic and pharmacodynamic assessments to find alternative treatments for this patient population.
Data from Tumor Cell–Autonomous SHP2 Contributes to Immune Suppression in Metastatic Breast Cancer
Authors: Chen Hao , Cresswell Gregory M. , Libring Sarah , Ayers Mitchell G. , Miao Jinmin , Zhang Zhong-Yin , Solorio Luis , Ratliff Timothy L. , Wendt Michael K.
Published: April 2023

SH2 containing protein tyrosine phosphatase-2 (SHP2) is recognized as a druggable oncogenic phosphatase that is expressed in both tumor cells and immune cells. How tumor cell–autonomous SHP2 contributes to an immunosuppressive tumor microenvironment (TME) and therapeutic failure of immune checkpoint blockades in metastatic breast cancer (MBC) is not fully understood. Herein, we utilized systemic SHP2 inhibition and inducible genetic depletion of SHP2 to investigate immune reprogramming during SHP2 targeting. Pharmacologic inhibition of SHP2 sensitized MBC cells growing in the lung to α-programmed death ligand 1 (α-PD-L1) antibody treatment via relieving T-cell exhaustion induced by checkpoint blockade. Tumor cell–specific depletion of SHP2 similarly reduced pulmonary metastasis and also relieved exhaustion markers on CD8+ and CD4+ cells. Both systemic SHP2 inhibition and tumor cell–autonomous SHP2 depletion reduced tumor-infiltrated CD4+ T cells and M2-polarized tumor-associated macrophages. Analysis of TCGA datasets revealed that phosphorylation of SHP2 is important for immune-cell infiltration, T-cell activation and antigen presentation. To investigate this mechanistically, we conducted in vitro T-cell killing assays, which demonstrated that pretreatment of tumor cells with FGF2 and PDGF reduced the cytotoxicity of CD8+ T cells in a SHP2-dependent manner. Both growth factor receptor signaling and three-dimensional culture conditions transcriptionally induced PD-L1 via SHP2. Finally, SHP2 inhibition reduced MAPK signaling and enhanced STAT1 signaling, preventing growth factor–mediated suppression of MHC class I. Overall, our findings support the conclusion that tumor cell–autonomous SHP2 is a key signaling node utilized by MBC cells to engage immune-suppressive mechanisms in response to diverse signaling inputs from TME.
Significance:
Findings present inhibition of SHP2 as a therapeutic option to limit breast cancer metastasis by promoting antitumor immunity.
Data from Avian Paramyxovirus 4 Antitumor Activity Leads to Complete Remissions and Long-term Protective Memory in Preclinical Melanoma and Colon Carcinoma Models
Authors: Javaheri Aryana , Bykov Yonina , Mena Ignacio , García-Sastre Adolfo , Cuadrado-Castano Sara
Published: April 2023

Avulaviruses represent a diverse subfamily of nonsegmented negative-strand RNA viruses infecting avian species worldwide. To date, 22 different serotypes have been identified in a variety of avian hosts, including wild and domestic birds. APMV-1 (Avian Paramyxovirus 1), also known as Newcastle disease virus (NDV), is the only avulavirus that has been extensively characterized because of its relevance for the poultry industry and, more recently, its inherent oncolytic activity and potential as a cancer therapeutic. An array of both naturally occurring and recombinant APMV-1 strains has been tested in different preclinical models and clinical trials, highlighting NDV as a promising viral agent for human cancer therapy. To date, the oncolytic potential of other closely related avulaviruses remains unknown. Here, we have examined the in vivo antitumor capability of prototype strains of APMV serotypes -2, -3, -4, -6, -7, -8, and -9 in syngeneic murine colon carcinoma and melanoma tumor models. Our studies have identified APMV-4 Duck/Hong Kong/D3/1975 virus as a novel oncolytic agent with greater therapeutic potential than one of the NDV clinical candidate strains, La Sota. Intratumoral administration of the naturally occurring APMV-4 virus significantly extends survival, promotes complete remission, and confers protection against rechallenge in both murine colon carcinoma and melanoma tumor models. Furthermore, we have designed a plasmid rescue strategy that allows us to develop recombinant APMV-4–based viruses. The infectious clone rAPMV-4 preserves the extraordinary antitumor capacity of its natural counterpart, paving the way to a promising next generation of viral therapeutics.
Significance:
Discovery of the oncolytic properties of APMV-4 Duck/Hong Kong/D3/1975: a novel cancer therapeutic with natural capacity to exert complete remission and long-term antitumor protection in syngeneic mouse cancer models.
Data from Patients with Lung Cancer of Different Racial Backgrounds Harbor Distinct Immune Cell Profiles
Authors: Xu Yitian , Zhang Licheng , Thaiparambil Jose , Mai Sunny , Perera Dimuthu Nuwan , Zhang Jilu , Pan Ping-Ying , Coarfa Cristian , Ramos Kenneth , Chen Shu-Hsia , El-Zein Randa
Published: April 2023

Tumors accumulated with infiltrated immune cells (hot tumors) have a higher response rate to immune checkpoint blockade, when compared with those with minimal T-cell infiltration (cold tumors). We report here that patients with lung cancer with different racial backgrounds harbored distinct immune cell profiles in the tumor microenvironment. Compared with African Americans (AA), Caucasian Americans (CA) exhibited increased immune cell infiltration and vasculature, and increased survival. Changes of survival and immune profile were most pronounced among active smokers and nonsmokers, compared with former smokers and total patients. Neighborhood analysis showed that immune cells accumulated around cancer cells in CAs but not AAs. Our findings reveal intrinsic biological differences between AA and CA patients with lung cancer, suggesting that treatment plans should be tailored for patients with different racial backgrounds.
Significance:
We report biological racial differences among patients with lung cancer where Caucasians present a hot tumor microenvironment compared with cold tumor in AAs. Treatment plans should be customized to maximize therapeutic outcomes.
Data from Assessment of Colorectal Cancer Screening Disparities in U.S. Men and Women Using a Demographically Representative Sample
Authors: Shah Sumit K. , Narcisse Marie-Rachelle , Hallgren Emily , Felix Holly C. , McElfish Pearl A.
Published: April 2023

Timely receipt of colorectal cancer screening can reduce morbidity and mortality. This is the first known study to adopt Andersen's model of health services use to identify factors associated with colorectal cancer screening among U.S. adults. The data from National Health Interview Survey from 2019 was utilized to conduct the analyses. Multivariable logistic regression was used to separately analyze data from 7,503 age-eligible women and 6,486 age-eligible men. We found similar colorectal cancer screening levels among men (57.7%) and women (57.6%). Factors associated with higher screening odds in women were older age, married/cohabitating with a partner, Black race, >bachelor's degree, having a usual source of care, and personal cancer history. Factors associated with lower odds for women were American Indian/Alaska Native race, living in the United States for ≤10 years, ≤138% federal poverty level (FPL), uninsured or having Medicare, and in fair/poor health. For men, factors associated with higher screening odds were older age, homosexuality, married/cohabitating with a partner, Black race, >high school/general educational development education, having military insurance, having a usual source of care, and personal cancer history. Factors associated with lower odds for men were being a foreign-born U.S. resident, living in the South or Midwest, ≤138% FPL, and being uninsured or having other insurance. Despite lower screening rates in the past, Black adults show a significantly higher likelihood of colorectal cancer screening than White adults; yet, screening disparities remain in certain other groups. Colorectal cancer screening efforts should continue to target groups with lower screening rates to eliminate screening disparities.
Significance:
Timely receipt of colorectal cancer screening can reduce morbidity and mortality. Identification of populations and domains of factors associated with colorectal cancer screening receipt among men and women can help future interventions to alleviate impeding factors and target screening promotion efforts in populations not adherent with screening guidelines.
Data from The Combination of Radiotherapy and Complement C3a Inhibition Potentiates Natural Killer cell Functions Against Pancreatic Cancer
Authors: Sodji Quaovi H. , Nambiar Dhanya K. , Viswanathan Vignesh , von Eyben Rie , Colburg Deana , Binkley Michael S. , Li Caiyun G. , Olcina Monica M. , Chang Daniel T. , Le Quynh-Thu , Giaccia Amato J.
Published: April 2023

Pancreatic cancer is one of the deadliest cancers, against which current immunotherapy strategies are not effective. Herein, we analyzed the immune cell composition of the tumor microenvironment of pancreatic cancer samples in The Cancer Genome Atlas and found that the presence of intratumoral natural killer (NK) cells correlates with survival. Subsequent analysis also indicated that NK cell exclusion from the microenvironment is found in a high percentage of clinical pancreatic cancers and in preclinical models of pancreatic cancer. Mechanistically, NK cell exclusion is regulated in part by complement C3a and its receptor signaling. Inhibition of the C3a receptor enhances NK cell infiltration in syngeneic mouse models of pancreatic cancer resulting in tumor growth delay. However, tumor growth inhibition mediated by NK cells is not sufficient alone for complete tumor regression, but is potentiated when combined with radiotherapy. Our findings indicate that although C3a inhibition is a promising approach to enhance NK cell–based immunotherapy against pancreatic cancer, its combination with radiotherapy holds greater therapeutic benefit.
Significance:
Immunotherapeutic agents are not effective against pancreatic cancer. We show that the inhibition of complement C3a enhances NK cell infiltration in preclinical models of pancreatic cancer, resulting in tumor growth delay. This effect is further potentiated by radiotherapy, thereby leading to significant antitumor activity compared with either therapy alone.
Data from Mitochondrial Matrix Protease ClpP Agonists Inhibit Cancer Stem Cell Function in Breast Cancer Cells by Disrupting Mitochondrial Homeostasis
Authors: Greer Yoshimi Endo , Hernandez Lidia , Fennell Emily M.J. , Kundu Manjari , Voeller Donna , Chari Raj , Gilbert Samuel F. , Gilbert Thomas S.K. , Ratnayake Shashikala , Tang Binwu , Hafner Markus , Chen Qingrong , Meerzaman Daoud , Iwanowicz Edwin , Annunziata Christina M. , Graves Lee M. , Lipkowitz Stanley
Published: April 2023

Mitochondria are multifaceted organelles which are important for bioenergetics, biosynthesis, and signaling in metazoans. Mitochondrial functions are frequently altered in cancer to promote both the energy and the necessary metabolic intermediates for biosynthesis required for tumor growth. Cancer stem cells (CSC) contribute to chemotherapy resistance, relapse, and metastasis. Recent studies have shown that while non-stem, bulk cancer cells utilize glycolysis, breast CSCs are more dependent on oxidative phosphorylation (OxPhos) and therefore targeting mitochondria may inhibit CSC function. We previously reported that small molecule ONC201, which is an agonist for the mitochondrial caseinolytic protease (ClpP), induces mitochondrial dysfunction in breast cancer cells. In this study, we report that ClpP agonists inhibit breast cancer cell proliferation and CSC function in vitro and in vivo. Mechanistically, we found that OxPhos inhibition downregulates multiple pathways required for CSC function, such as the mevalonate pathway, YAP, Myc, and the HIF pathway. ClpP agonists showed significantly greater inhibitory effect on CSC functions compared with other mitochondria-targeting drugs. Further studies showed that ClpP agonists deplete NAD(P)+ and NAD(P)H, induce redox imbalance, dysregulate one-carbon metabolism and proline biosynthesis. Downregulation of these pathways by ClpP agonists further contribute to the inhibition of CSC function. In conclusion, ClpP agonists inhibit breast CSC functions by disrupting mitochondrial homeostasis in breast cancer cells and inhibiting multiple pathways critical to CSC function.
Significance:
ClpP agonists disrupt mitochondrial homeostasis by activating mitochondrial matrix protease ClpP. We report that ClpP agonists inhibit cell growth and CSC functions in breast cancer models by modulating multiple metabolic pathways essential to CSC function.
Data from Expanding the Prostate Cancer Cell Line Repertoire with ACRJ-PC28, an AR-negative Neuroendocrine Cell Line Derived From an African-Caribbean Patient
Authors: Valentine Henkel , Aiken William , Morrison Belinda , Zhao Ziran , Fowle Holly , Wasserman Jason S. , Thompson Elon , Chin Warren , Young Mark , Clarke Shannique , Gibbs Denise , Harrison Sharon , McLaughlin Wayne , Kwok Tim , Jin Fang , Campbell Kerry S. , Horvath Anelia , Thompson Rory , Lee Norman H. , Zhou Yan , Graña Xavier , Ragin Camille , Badal Simone
Published: April 2023

Prostate cancer cell lines from diverse backgrounds are important to addressing disparities in prostate cancer incidence and mortality rates among Black men. ACRJ-PC28 was developed from a transrectal needle biopsy and established via inactivation of the CDKN2A locus and simultaneous expression of human telomerase. Characterization assays included growth curve analysis, immunoblots, IHC, three-dimensional cultures, immunofluorescence imaging, confocal microscopy, flow cytometry, whole-genome sequencing (WGS), and RNA sequencing (RNA-seq). ACRJ-PC28 has been passaged more than 40 times in vitro over 10 months with a doubling time of 45 hours. Short tandem repeat profiling confirmed the novelty and human origin of the cell line. RNA-seq confirmed the expression of prostate specific genes alpha-methylacyl-CoA racemase (AMACR) and NKX3.1 and neuroendocrine specific markers synaptophysin and enolase 2 (ENO2) and IHC confirmed the presence of AMACR. Immunoblots indicated the cell line is of basal-luminal type; expresses p53 and pRB and is androgen receptor (AR) negative. WGS confirmed the absence of exonic mutations and the presence of intronic variants that appear to not affect function of AR, p53, and pRB. RNA-seq data revealed numerous TP53 and RB1 mRNA splice variants and the lack of AR mRNA expression. This is consistent with retention of p53 function in response to DNA damage and pRB function in response to contact inhibition. Soft agar anchorage-independent analysis indicated that the cells are transformed, confirmed by principal component analysis where ACRJ-PC28 cells cluster alongside other prostate cancer tumor tissues, yet was distinct. The novel methodology described should advance prostate cell line development, addressing the disparity in prostate cancer among Black men.
Significance:
Cell line development continues to attract less than 10% success rate. More than 98% of prostate cancer cell lines are from White men. This may contribute to the poorer response by Black men with prostate cancer to therapy compared with White men with prostate cancer, increasing overall survivorship among White men. The methodology described here to develop ACRJ-PC28, should advance the presence of Black prostate cancer cell lines thereby addressing prostate cancer disparity.
Data from Real-world Validation of TMB and Microsatellite Instability as Predictive Biomarkers of Immune Checkpoint Inhibitor Effectiveness in Advanced Gastroesophageal Cancer
Authors: Graf Ryon P. , Fisher Virginia , Creeden James , Schrock Alexa B. , Ross Jeffrey S. , Nimeiri Halla , Oxnard Geoffrey R. , Klempner Samuel J.
Published: April 2023

Patients with advanced gastroesophageal cancer (mEG) and tumor mutational burden ≥10 mut/Mb (TMB ≥ 10) have more favorable outcomes on immune checkpoint inhibitor (ICPI) monotherapy compared with chemotherapy in subgroup analyses of randomized controlled trials. We sought to evaluate the robustness of these associations in real-world settings where patients and practices are more diverse. A total of 362 2 L and 692 1 L patients, respectively received ICPI (n = 99, 33) or chemotherapy (n = 263, 659) across approximately 280 U.S. academic or community-based cancer clinics March 2014–July 2021. Deidentified data were captured into a real-world clinico-genomic database. All patients underwent Foundation Medicine testing. Time to next treatment (TTNT) and overall survival (OS) comparing ICPI versus chemotherapy were adjusted for treatment assignment imbalances using propensity scores. 2L: TMB ≥ 10 had more favorable TTNT [median 24 vs. 4.1 months; HR: 0.19; 95% confidence interval (CI): 0.09–0.44; P = 0.0001] and OS (median 43.1 vs. 6.2 months; HR: 0.24; 95% CI: 0.011–0.54; P = 0.0005), TMB < 10 did not (P > 0.05). 1L: TMB ≥ 10 had more favorable TTNT (not reached vs. median 4.1 months; HR: 0.13; 95% CI: 0.03–0.48; P = 0.0024) and OS (not reached vs. median 17.1 months; HR: 0.30; 95% CI: 0.08–1.14; P = 0.078), TMB < 10 had less favorable TTNT (median 2.8 vs. 6.5 months; HR: 2.36; 95% CI: 1.25–4.45; P = 0.008) and OS (median 4.5 vs. 13.1 months; HR: 1.82, 95% CI: 0.87–3.81; P = 0.11). TMB ≥ 10 robustly identifies patients with mEG with more favorable outcomes on 2 L ICPI monotherapy versus chemotherapy. 1 L data are more limited, but effects are consistent with 2L.
Significance:
Using real-world data, we sought to evaluate robustness of these clinical associations using the same assay platform and biomarker cut-off point used in both clinical trials and pan-tumor CDx approvals for later treatment lines. TMB ≥ 10 robustly identified patients with mEG with more favorable outcomes on ICPI monotherapy versus chemotherapy and suggests this subset of patients could be targeted for further trial development.