Development Of Solid Tumors Research Articles

HER2-Overexpressing/Amplified Breast Cancer as a Testing Ground for Antibody-Drug Conjugate Drug Development in Solid Tumors.

Efficacy data from the KATHERINE clinical trial, comparing the HER2-directed antibody-drug conjugate (ADC) ado-trastuzumab emtansine (T-DM1) to trastuzumab in patients with early-stage HER2-amplified/overexpressing breast cancer with residual disease after neoadjuvant therapy, demonstrates superiority of T-DM1 (HR for invasive disease or death, 0.50; P < 0.001). This establishes foundational precedent for ADCs as effective therapy for treatment of subclinical micrometastasis in an adjuvant (or post-neoadjuvant) early-stage solid tumor setting. Despite this achievement, general principles from proposed systems pharmacokinetic modeling for intracellular processing of ADCs indicate potential shortcomings of T-DM1: (i) C max limited by toxicities; (ii) slow internalization rate; (iii) resistance mechanisms due to defects in intracellular trafficking [loss of lysosomal transporter solute carrier family 46 member 3, (SLC46A3)], and increased expression of drug transporters MDR1 and MRP1; and (iv) lack of payload bystander effects limiting utility in tumors with heterogeneous HER2 expression. These handicaps may explain the inferiority of T-DM1-based therapy in the neoadjuvant and first-line metastatic HER2+ breast cancer settings, and lack of superiority to chemotherapy in HER2+ advanced gastric cancer. In this review, we discuss how each of these limitations is being addressed by manipulating internalization and trafficking using HER2:HER2 bispecific or biparatopic antibody backbones, using site-specific, fixed DAR conjugation chemistry, and payload swapping to exploit alternative intracellular targets and to promote bystander effects. Newer HER2-directed ADCs have impressive clinical activity even against tumors with lower levels of HER2 receptor expression. Finally, we highlight ongoing clinical efforts to combine HER2 ADCs with other treatment modalities, including chemotherapy, molecularly targeted therapies, and immunotherapy.

PIK3CA gene aberrancy and role in targeted therapy of solid malignancies.

Phosphoinositide kinases (PIKs) are a group of lipid kinases that are important upstream activators of various signaling pathways that drive oncogenesis. Hyperactivation of the PI3K/AKT/mTOR pathways-either via mutations or genomic amplification-confers key oncogenic activity, essential for the development and progression of several solid tumors. Alterations in the PIK3CA gene are associated with poor prognosis of solid malignancies. Contradictory reports exist in the literature regarding the prognostic value of PIK3CA in aggressive cancers, but most available data highlights an important role of PIK3CA mutation in mediating tumorigenesis via increased signaling of the PI3K/AKT/mTOR survival pathway. Several inhibitors of PI3K/AKT/mTOR pathways have been investigated as potential therapeutic options in solid malignancies. This article reviews the role of PIK3CA mutations and inhibitors of the PI3K/AKT/mTOR pathway in cancer and examines association with the clinico-pathological parameters and prognosis.

Structure-Based Design and Identification of FT-2102 (Olutasidenib), a Potent Mutant-Selective IDH1 Inhibitor.

Inhibition of mutant IDH1 is being evaluated clinically as a treatment option for oncology. Here we describe the structure-based design and optimization of quinoline lead compounds to identify FT-2102, a potent, orally bioavailable, brain penetrant, and selective mIDH1 inhibitor. FT-2102 has excellent ADME/PK properties and reduces 2-hydroxyglutarate levels in an mIDH1 xenograft tumor model. This compound has been selected as a candidate for clinical development in hematologic malignancies, solid tumors, and gliomas with mIDH1.

Overexpression of microRNA-155 enhances the efficacy of dendritic cell vaccine against breast cancer

ABSTRACT MicroRNA 155 (miR-155) plays important roles in the regulation of the development and functions of a variety of immune cells. We previously revealed a vital role of miR-155 in regulating the function of dendritic cells (DCs) in breast cancer. miR-155 deficiency in DCs impaired their maturation, migration, cytokine production, and ability to activate T cells. In the current study, to exploit the therapeutic value of miR-155 for breast cancer, we examined the impact of overexpression of miR-155 on antitumor responses generated by DC vaccines. We boosted miR-155 expression in DCs by generating a miR-155 transgenic mouse strain (miR-155tg) or using lentivirus transduction. DCs overexpressing miR-155 exhibited enhanced functions in response to tumor antigens. Using miR-155 overexpressing DCs, we generated a DC vaccine and found that the vaccine resulted in enhanced antitumor immunity against established breast cancers in mice, demonstrated by increased effector T cells in the mice, suppressed tumor growth, and drastically reduced lung metastasis. Our current study suggests that in future DC vaccine development for breast cancer or other solid tumors, introducing forced miR155 overexpression in DCs via various approaches such as viral transduction or nanoparticle delivery, as well as including other adjuvant agents such as TLR ligands or immune stimulating cytokines, may unleash the full therapeutic potential of the DC vaccines.

EphB2 represents an independent prognostic marker in patients with gastric cancer and promotes tumour cell aggressiveness.

Dysregulated expression of ephrin type-B receptor 2 (EphB2) has been linked with the development and progression of solid tumours. In the current study, we attempted to investigate the clinical relevance in GC and the effect of EphB2 expression on gastric cancer (GC) cells. EphB2 protein levels in GC and benign gastric tissues were determined using immunohistochemistry. EphB2 transcript expression in a GC cohort with GC tissue samples (n=171) and paired adjacent normal gastric tissues (n=97) was determined using qPCR. The EphB2 expression was over-activated using a CRISPR activator for the investigation of its cellular function. The expression levels of the EphB2 protein in the tumour tissues of tissue arrays were higher than the benign non-cancerous gastric tissues (P<0.05). EphB2 mRNA expression in GC tissues was also significantly elevated when compared with adjacent non-cancerous tissues (P<0.01). EphB2 activation promoted the migration and invasion abilities of the GC cell lines (P<0.01, respectively). In contrast, EphB2 activation significantly decreased the adhesion in GC cells (P<0.0001, respectively). The enrichment analysis of the correlated genes in a GC cohort indicates that EphB2 may function through mediating the cytokine-cytokine interaction, JAK-STAT and TP53 signaling pathways. In conclusion, EphB2 represents as a novel independent prognostic marker in GC. And activation of the EphB2 gene expression elevated the levels of migration and invasion, but suppressed adhesion of GC cells, indicating that EphB2 may act as a tumour promotor in GC. Our findings thus provide fundamental evidence for the consideration of the therapeutic potential of targeting EphB2 in GC.

Malvidin Abrogates Oxidative Stress and Inflammatory Mediators to Inhibit Solid and Ascitic Tumor Development in Mice.

The anticancer activity of malvidin was studied in Dalton's lymphoma ascites (DLA)-induced solid and ascitic tumor mice models. Malvidin is a natural compound belonging to the family of O-methylated anthocyanidin and plays a predominant role in regulating both short- and long-term cellular activities. Animals were injected with DLA cells (1.5 × 106 cells/animal) to induce solid and ascitic tumors. The administration of malvidin (5 mg/kg bw and 10 mg/kg bw) was carried out for 10 consecutive days from the day of tumor induction for both solid and ascitic tumors. Cyclophosphamide, CTX (25 mg/kg bw), used as the standard drug, was also administered for 10 consecutive days. Treatment with malvidin showed a significant reduction in tumor volume and elevated white blood cell (WBC) count when compared to the DLA-bearing control animals. The treatment also maintained the body weight and hemoglobin level, and decreases in aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT) were also noted. This investigation also reported the decreased levels of cellular glutathione (GSH) in ascitic tumor groups. Malvidin reduced inflammatory mediator and cytokine levels, such as tumor necrosis factor level alpha (TNF-α) and interleukin-6 (IL-6), which serve as molecular targets for cancer prevention. A decrease in the level of reactive oxygen species (ROS), like nitric oxide (NO), was observed. Histopathological examination revealed altered morphological changes in tumor tissue and the alleviation of hepatic architecture due to DLA. Immunohistochemical analysis revealed the inhibition of iNOS. This study demonstrated that malvidin exhibited significant in vivo antitumor activity and that it was reasonably imputable to its increasing endogenous mechanism. We accent the pertinence of malvidin as a potential naturally derived drug target for tumor control.

Transmembrane protease serine 4: An emergent diagnostic biomarker and Therapeutic drug target for cancer

Proteases expressed in healthy cells are significant for performing necessary biological functions. There exists equilibrium among proteases and anti-proteases in living systems, thus interruption of equilibrium results in numerous disorders such as cancer. One of the signs of cancer development is proteolysis due to dysregulation of proteases. All five categories of proteases including cysteine, aspartate, threonine, matrix metalloproteases and serine have been associated with solid tumor instigation, growth, development, invasiveness and metastasis. The set of genes expressed in neoplasm development is well-known as cancer ‘degradome’. Transmembrane protease serine 4 (TMPRSS4), a novel type II transmembrane serine protease present at the cellular membrane is upregulated in numerous kinds of human carcinoma and have an irreplaceable role in tumor development. Hepsin, matriptase and TMPRSS2 are other cancer-associated proteases interconnected to TMPRSS4.TMPRSS4 can be used as an emerging therapeutic drug target in human malignant neoplasms as over expression of TMPRSS4 contribute significantly in processes of cancer development including vascularization, metastasis and invasion. Nevertheless, the biological function of TMPRSS4 in solid tumors continues to be ambiguous. In this review, we will discuss about physiological function, gene expression, clinical significance and regulation mechanism of TMPRSS4 in cancer development. Our study provides the rationale for targeting TMPRSS4 in cancer.

PIK3CA Gene Mutations in Solid Malignancies: Association with Clinicopathological Parameters and Prognosis.

Phosphoinositide kinases (PIKs) are a group of lipid kinases that are important upstream activators of various significant signaling pathways. Hyperactivation of the PI3K/AKT/mTOR pathways—either via mutations or genomic amplification—confers key oncogenic activity, essential for the development and progression of several solid tumors. Alterations in the PIK3CA gene are associated with poor prognosis of solid malignancies. Although the literature reports contradictory prognostic values of PIK3CA in aggressive cancers, most of the available data highlight the important role of PIK3CA mutation in mediating tumorigenesis via increased signaling of the PI3K/AKT/mTOR survival pathway. Several inhibitors of PI3K/AKT/mTOR pathways are investigated as potential therapeutic options in solid malignancies. This article reviews the role of PIK3CA mutations and inhibitors of PI3K/AKT/mTOR pathways in major cancer types and examines its association with clinicopathological parameters and prognosis.

Abstract I03: Immune contexture of human pancreatic cancer

Abstract The concept that leukocytes are critical components of solid tumors is now generally accepted; however, their role(s) in regulating aspects of neoplastic progression, and/or response to cytotoxic, targeted, and/or immune therapy is only beginning to be understood. Utilizing de novo mouse models of organ-specific solid tumor development (mammary, cutaneous, and pancreas carcinomas and mesothelioma), we now appreciate that adaptive leukocytes differentially regulate myeloid cell recruitment, activation, and effector function, and in turn, activated tumor-infiltrating myeloid cells engage tissue-based programs to foster malignancy and repress antitumor immunity by a diversity of mechanisms. Treatment of tumor-bearing mice with therapeutic agents that disrupt lymphocyte-myeloid cell interaction, myeloid cell activation, or myeloid cell functionality generally slow primary tumor growth kinetics when combined with cytotoxic therapy; however, their impact on metastases is variable. Similar to organ-specific regulatory programs co-opted to foster primary tumor growth, regulation of metastatic seeding and outgrowth is also regulated by tissue- and organ-specific mechanisms. Based on this, it stands to reason that therapeutic strategies may not be efficacious in both primary and metastatic locations. To be presented will be our recent insights into organ- and tissue-specific regulation of primary and metastatic cancer development by adaptive and innate immune cells, how systemic regulation of humoral immunity and complement-mediated pathways regulate pro- versus antitumor immune responses, and new studies evaluating how attenuating protumor properties of select lymphoid and myeloid cells can be exploited to enhance therapeutic responses to cytotoxic and immune-based therapy. (LMC acknowledges generous support from the NIH/NCI, the Department of Defense Breast Cancer Research Program, Susan G. Komen Foundation, the Breast Cancer Research Foundation, and the Brenden-Colson Center for Pancreatic Health.) Citation Format: Lisa M. Coussens. Immune contexture of human pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr I03.

Relief of tumor hypoxia unleashes the tumoricidal potential of neutrophils.

Polymorphonuclear neutrophils (PMNs) are increasingly recognized to influence solid tumor development, but why their effects are so context dependent and even frequently divergent remains poorly understood. Using an autochthonous mouse model of uterine cancer and the administration of respiratory hyperoxia as a means to improve tumor oxygenation, we provide in vivo evidence that hypoxia is a potent determinant of tumor-associated PMN phenotypes and direct PMN-tumor cell interactions. Upon relief of tumor hypoxia, PMNs were recruited less intensely to the tumor-bearing uterus, but the recruited cells much more effectively killed tumor cells, an activity our data moreover suggested was mediated via their production of NADPH oxidase-derived reactive oxygen species and MMP-9. Simultaneously, their ability to promote tumor cell proliferation, which appeared to be mediated via their production of neutrophil elastase, was rendered less effective. Relieving tumor hypoxia thus greatly improved net PMN-dependent tumor control, leading to a massive reduction in tumor burden. Remarkably, this outcome was T cell independent. Together, these findings identify key hypoxia-regulated molecular mechanisms through which PMNs directly induce tumor cell death and proliferation in vivo and suggest that the contrasting properties of PMNs in different tumor settings may in part reflect the effects of hypoxia on direct PMN-tumor cell interactions.

Targeting Sirt6 with OSS_128167 Displays Anti-Tumor Activities in Diffuse Large B-Cell Lymphoma through Down-Regulation of PI3K Signaling

Introduction Sirt6, a member of the mammalian sirtuins family, functions as a highly conserved ADP-ribosylase and NAD+ dependent deacylase. Evidence from recent years indicates that Sirt6 is closely related to the occurrence and development of various solid tumors and multiple myeloma (MM). OSS_128167 is a novel small molecular inhibitor specifically targeting Sirt6, and induced chemosensitization in MM cells. Nevertheless, the role of Sirt6 in lymphoid malignancies is still unclear. Herein, we investigated the function of Sirt6 and identified the anti-tumor effects of OSS_128167 in diffuse large B-cell lymphoma (DLBCL). Methods Immunohistochemistry (IHC) was conducted to assess the expression of Sirt6 on paraffin-embedded tissues from 70 de novo DLBCL patients and 35 reactive hyperplasia patients with informed contents. Microarray dataset GSE32918 was obtained from Gene Expression Omnibus and survival analysis was performed. Lentivirus vectors either encoding shSirt6, lvSirt6 or empty lentiviral vector were stably transfected into DLBCL cells. shSirt6 transfected or shControl transfected LY1 cell samples were performed RNA sequencing (RNA-seq) analysis, functional enrichment analyses of gene ontology (GO) and gene set enrichment analysis (GSEA). DLBCL cells were subcutaneously injected to SCID-Beige mice to establish xenograft models. All animal experiments were performed in accordance with the principles of the Institutional Animal Care. A p value of less than 0.05 was interpreted as having statistical significance. Results Aberrantly overexpression of Sirt6 was confirmed in DLBCL tissues compared with reactive hyperplasia by IHC staining (Fig 1a). The expression level of Sirt6 was revealed in significant positive correlation with advanced age (p=0.009), Ann Arbor stage (p=0.036) and IPI score (p=0.045, Fig. 1b). Sirt6 high expression was turned up to be correlated with reduced overall survival of enrolled patients according to GSE32918 (n=249, Fig. 1c). Stable shSirt6 transfected DLBCL cells exhibited growth suppression compared to those transfected with empty vector in vitro (Fig. 2a) and in vivo (Fig. 2b-c). Lower expression level of Ki-67 was confirmed in the xenograft tumor tissues derived from shSirt6 cells by IHC staining (Fig. 2d). Sirt6 knockdown caused enforced apoptosis rates, induced G2/M phase arrest (Fig. 2e-f) and enhanced sensitivity to Doxorubicin (ADR) and bendamustine (Fig. 2g-h). These results were further confirmed in GO analysis according to RNA-seq (Fig. 2i) and WB (Fig. 2j). The exciting finding was, OSS_128167 obviously decreased cell proliferation (Fig. 3a), induced cell apoptosis (Fig. 3b) and blocked cell cycle (Fig. 3c) in DLBCL cell lines. Addition to ADR or bendamustine with 100µM OSS_128167 exhibited enhanced cytotoxicity in DLBCL cells (p&lt; 0.05; Fig. 3d-e). Xenograft DLBCL mice model were treated with intraperitoneal injection of either OSS_128167 or a control vehicle every two days for 2 weeks. Consistent with our in vitro results, obviously decreased tumor growth were observed in the OSS_128167 group (Fig. 3f). Also, lowly expression level of c-Myc was found in OSS_128167 treated mice (Fig. 3g). We then investigated the underlying mechanism driving the tumor genesis potential of Sirt6. In accordance with the GSEA analysis, we observed that the phosphorylation of PI3K p110α and its downstream targets, including Akt (Ser473) and mTOR protein, were dramatically decreased in Sirt6 knockdown cells than in the control cells (Fig. 4a-b). In vivo western blotting analysis further confirmed it (Fig. 4c). The Sirt6 deletion-induced reductive of cell viability was only fewer restored by IGF-1 (Fig. 4d). Conclusion At present, the function of Sirt6 in tumorigenesis is still controversial. Our findings demonstrated for the first time the oncogenic role of Sirt6 in the pathogenesis of DLBCL. High expression of Sirt6 may serve as a prognostic marker for inferior outcome in DLBCL patients. OSS_128167, a novel targeted inhibitor of Sirt6, exerted excellent anti-lymphoma effects via activating PI3K/Akt/mTOR signaling. In addition, blockade of Sirt6 expression enhanced the sensitivity of DLBCL cells to chemotherapeutic agents. These findings provide mechanistic insights into the oncogenic activity of Sirt6 and highlighted the potency of OSS_128167 for novel therapeutic strategies in DLBCL. Disclosures No relevant conflicts of interest to declare.

Natural Sesquiterpene Lactones Enhance Chemosensitivity of Tumor Cells through Redox Regulation of STAT3 Signaling.

STAT3 is a nuclear transcription factor that regulates genes involved in cell cycle, cell survival, and immune response. Although STAT3 activation drives cells to physiological response, its deregulation is often associated with the development and progression of many solid and hematological tumors as well as with drug resistance. STAT3 is a redox-sensitive protein, and its activation state is related to intracellular GSH levels. Under oxidative conditions, STAT3 activity is regulated by S-glutathionylation, a reversible posttranslational modification of cysteine residues. Compounds able to suppress STAT3 activation and, on the other hand, to modulate intracellular redox homeostasis may potentially improve cancer treatment outcome. Nowadays, about 35% of commercial drugs are natural compounds that derive from plant extracts used in phytotherapy and traditional medicine. Sesquiterpene lactones are an interesting chemical group of plant-derived compounds often employed in traditional medicine against inflammation and cancer. This review focuses on sesquiterpene lactones able to downmodulate STAT3 signaling leading to an antitumor effect and correlates the anti-STAT3 activity with their ability to decrease GSH levels in cancer cells. These properties make them lead compounds for the development of a new therapeutic strategy for cancer treatment.

Global profiling of O-GlcNAcylated and/or phosphorylated proteins in hepatoblastoma

O-linked-β-N-acetylglucosamine (O-GlcNAc) glycosylation (O-GlcNAcylation) and phosphorylation are critical posttranslational modifications that are involved in regulating the functions of proteins involved in tumorigenesis and the development of various solid tumors. However, a detailed characterization of the patterns of these modifications at the peptide or protein level in hepatoblastoma (HB), a highly malignant primary hepatic tumor with an extremely low incidence in children, has not been performed. Here, we examined O-GlcNAc-modified or phospho-modified peptides and proteins in HB through quantitative proteomic analysis of HB tissues and paired normal liver tissues. Our results identified 114 O-GlcNAcylated peptides belonging to 78 proteins and 3494 phosphorylated peptides in 2088 proteins. Interestingly, 41 proteins were modified by both O-GlcNAcylation and phosphorylation. These proteins are involved in multiple molecular and cellular processes, including chromatin remodeling, transcription, translation, transportation, and organelle organization. In addition, we verified the accuracy of the proteomics results and found a competitive inhibitory effect between O-GlcNAcylation and phosphorylation of HSPB1. Further, O-GlcNAcylation modification of HSPB1 promoted proliferation and enhanced the chemotherapeutic resistance of HB cell lines in vitro. Collectively, our research suggests that O-GlcNAc-modified and/or phospho-modified proteins may play a crucial role in the pathogenesis of HB.

A CASE OF LEUKEMIA COMPLICATED BY NON-SMALL CELL LUNG CANCER

SESSION TITLE: Monday Fellow Case Report Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: 10/21/2019 02:30 PM - 03:15 PM INTRODUCTION: The occurrence of multiple primary cancers (MPCs) is rare. The diagnosis and treatment of MPCs is often challenging, and often, they cannot be treated simultaneously (1). We report a case of a patient with recurrent pre-B-cell acute lymphoblastic leukemia (pBALL) who was diagnosed with a new non-small cell lung carcinoma (NSCLC). CASE PRESENTATION: A 51 year old male with a remote history of testicular cancer s/p orchiectomy and cisplatin and recurrent pBALL presented with a 4 day history of shortness of breath, non-productive cough and fatigue. Twelve months prior, he was diagnosed with pBALL and treated with 1 cycle of cytarabine, dexamethasone, vincristine, daunorubicin, pegasparagasen and intrathecal methotrexate, and 4 cycles of cyclophosphamide, vincristine, doxorubicin, and dexamethasone, which he completed 2 months prior to presentation. A CT angiogram showed a 2.4 cm right parahilar mass (Figure 1). Bronchoscopy revealed an endobronchial lesion in the right upper lobe (Figure 2) and fine needle aspiration was performed. Endobronchial ultrasound was employed to perform transbronchial fine needle aspiration of station 11R (Figure 2). Immunohistochemistry showed positive staining for CK5/6 and CKAE1/3. P53 staining was also strongly positive in the malignant cells (Figure 3). These staining patterns supported a diagnosis of NSCLC. The patient was readmitted shortly after with recurrence of his pBALL. Unfortunately, given disease progression on imaging and by symptoms, the patient opted for hospice care. DISCUSSION: The prevalence of MPCs is uncertain, ranging between 0.734-11.7%(2). While MPCs are uncommon in general, the combination of hematologic and solid cancers is rare. The SEER database suggests a slight increased occurrence of lung cancer in patients with ALL compared to the general population (3). The etiology is not clear. The few cases that have been published highlight the association between hematologic cancers treated with various chemotherapy regimens and the development of subsequent solid tumors, or a possible hereditary component (1,3). CONCLUSIONS: Although it may seem redundant to biopsy a new lesion identified in a patient with malignancy, it is important that clinicians consider the possibility of MPCs in certain clinical contexts as they can complicate primary disease treatment and may limit treatment options of the new disease. Reference #1: Cui Y, Liu T, Zhou Y, et al. “Five cases report of solid tumor synchronously with hematologic malignancy.” Cancer Res Treat. 2012 Mar;44(1):63-8. https://doi.org/10.4143/crt.2012.44.1.63. Epub 2012 Mar 31. Reference #2: Demandante CG, Troyer DA, Miles TP. “Multiple primary malignant neoplasms: case report and a comprehensive review of the literature.” Am J Clin Oncol. 2003 Feb;26(1):79-83. Review. Reference #3: Shah, B. K. (2013). Second Primary Malignancies In Adult Acute Lymphoblastic Leukemia. Blood, 122(21), 3871. Accessed March 14, 2019. Retrieved from http://www.bloodjournal.org/content/122/21/3871. DISCLOSURES: No relevant relationships by Erum Arain, source=Web Response No relevant relationships by Amit Goyal, source=Web Response No relevant relationships by Michal Reid, source=Web Response

Growth and remodeling in highly stressed solid tumors

Growing biological media develop residual stresses to make compatible elastic and inelastic growth-induced deformations, which in turn remodel the tissue properties modifying the actual elastic moduli and transforming an initially isotropic and homogeneous material into a spatially inhomogeneous and anisotropic one. This process is crucial in solid tumor growth mechanobiology, the residual stresses directly influencing tumor aggressiveness, nutrients walkway, necrosis and angiogenesis. With this in mind, we here analyze the problem of a hyperelastic sphere undergoing finite heterogeneous growth, in cases of different boundary conditions and spherical symmetry. By following an analytical approach, we obtain the explicit expression of the tangent elasticity tensor at any point of the material body as a function of the prescribed growth, by involving a small-on-large procedure and exploiting exact solutions for layered media. The results allowed to gain several new insights into how growth-guided mechanical stresses and remodeling processes can influence the solid tumor development. In particular, we highlight that—under hypotheses consistent with mechanical and physiological conditions—auxetic (negative Poisson ratio) transformations of the elastic response of selected growing mass districts could occur and contribute to explain some not yet completely understood phenomena associated to solid tumors. The general approach proposed in the present work could be also helpfully employed to conceive composite materials where ad hoc pre-stress distributions can be designed to obtain auxetic or other selected mechanical properties.

Characterization and genotype-phenotype correlation of patients with Fanconi anemia in a multi-ethnic population.

Fanconi anemia (FA), an inherited bone marrow failure (BMF) syndrome, caused by mutations in DNA repair genes, is characterized by congenital anomalies, aplastic anemia, high risk of malignancies and extreme sensitivity to alkylating agents. We aimed to study the clinical presentation, molecular diagnosis and genotype-phenotype correlation among patients with FA from the Israeli inherited BMF registry. Overall, 111 patients of Arab (57%) and Jewish (43%) descent were followed for a median of 15 years (range: 0.1-49); 63% were offspring of consanguineous parents. One-hundred patients (90%) had at least one congenital anomaly; over 80% of the patients developed bone marrow failure; 53% underwent hematopoietic stem-cell transplantation; 33% of the patients developed cancer; no significant association was found between hematopoietic stem-cell transplant and solid tumor development. Nearly 95% of the patients tested had confirmed mutations in the Fanconi genes FANCA (67%), FANCC (13%), FANCG (14%), FANCJ (3%) and FANCD1 (2%), including twenty novel mutations. Patients with FANCA mutations developed cancer at a significantly older age compared to patients with mutations in other Fanconi genes (mean 18.5 and 5.2 years, respectively, P=0.001); however, the overall survival did not depend on the causative gene. We hereby describe a large national cohort of patients with FA, the vast majority genetically diagnosed. Our results suggest an older age for cancer development in patients with FANCA mutations and no increased incidence of solid tumors following hematopoietic stem-cell transplant. Further studies are needed to guide individual treatment and follow-up programs.

The effects of focal adhesion kinase and platelet-derived growth factor receptor beta inhibition in a patient-derived xenograft model of primary and metastatic Wilms tumor.

Aggressive therapies for patients with metastatic Wilms tumor (WT) with subsequent severe late effects warrant the search for novel therapies. The role of focal adhesion kinase (FAK), a non-receptor tyrosine kinase important in pediatric solid tumor development and progression, has not been examined in metastatic WT. Using a novel patient-derived xenograft (PDX) of a primary and matched, isogenic, metastatic WT, the hypothesis of the current study was that FAK would contribute to metastatic WT and small molecule inhibition would decrease tumor growth. Immunohistochemical staining, immunoblotting, cell viability and proliferation assays, cell cycle analysis, and cellular motility and attachment-independent growth assays were performed. FAK was present and phosphorylated in both WT PDXs and in the human samples from which they were derived. FAK inhibition decreased cellular survival, proliferation, and cell cycle progression in both PDXs but only significantly decreased migration, invasion, and attachment-independent growth in the primary WT PDX. Kinomic profiling revealed that platelet-derived growth factor receptor beta (PDGFRβ) may be affected by FAK inhibition in WT. Pharmacologic inhibition of FAK and PDGFRβ was synergistic in primary WT PDX cells. These findings broaden the knowledge of metastatic WT and support further investigations on the potential use of FAK and PDGFRβ inhibitors.

Aspirin targets P4HA2 through inhibiting NF-κB and LMCD1-AS1/let-7g to inhibit tumour growth and collagen deposition in hepatocellular carcinoma.

BackgroundAbnormal construction of the extracellular matrix (ECM) is intimately linked with carcinogenesis and the development of solid tumours, especially hepatocellular carcinoma (HCC). As the major component of the ECM, collagen plays a pivotal role in carcinogenesis. P4HA2, the essential enzyme during collagen formation, becomes an important target in HCC treatment. Here, we tried to decipher whether aspirin (ASA), a classic anti-inflammatory drug, could improve the prognosis of HCC through targeting P4HA2.MethodsWestern blotting, qRT-PCR assay, immunofluorescence staining, luciferase reporter gene assay, and ChIP assay were applied to demonstrate the molecular mechanism of the regulation of P4HA2 expression by aspirin. A mouse xenograft model, cell viability assay, colony formation assay, and immunohistochemistry analysis were used to evaluate the anti-fibrosis effect of aspirin through targeting the NF-κB/P4HA2 axis and LMCD1-AS1/let-7g/P4HA2 axis in vitro and in vivo. The TCGA database was used to evaluate the correlation among P4HA2, let-7g, LMCD1-AS1 and overall survival of HCC patients.FindingsIn xenograft mice, aspirin was capable of targeting P4HA2 to decrease collagen deposition, resulting in the inhibition of liver tumour growth. TCGA database analysis revealed the close association between a higher P4HA2 concentration in HCC patients and shorter overall survival or a higher cancer stage and the pathological grade. Mechanistically, NF-κB can bind to the promoter of P4HA2 to activate its transcription. Moreover, lncRNA LMCD1-AS1 functions as a molecular sponge of let-7g to post-transcriptionally induce the target gene of let-7g, namely, P4HA2.InterpretationOur findings disclose the novel role and regulatory mechanism of aspirin in the suppression of HCC by disrupting abnormal collagen deposition.Funds973 Program, National Natural Scientific Foundation of China, Fundamental Research Funds for the Central Universities, Project of Prevention and Control of Key Chronic Non-Infectious Diseases.

Abstract 614: Cytomegalovirus (CMV) reactivation and patient survival in head and neck cancer

Abstract There is building evidence that cytomegalovirus (CMV) may contribute to the development of solid tumors, however to date this has not been investigated in head and neck cancer (HNC). CMV is a highly prevalent, latent herpesvirus infecting over 50% of the population. CMV maintains latency in CD34+ cells, and recent work has demonstrated these latently infected cells preferentially differentiate into immunosuppressive monocytes. However, CMV is not solely immune suppressive as highly cytotoxic adaptive natural killer (NK) cells arise specifically in response to CMV reactivation. Here, we have investigated whether biomarkers of CMV reactivation are associated with patient survival in non-smoking HNC (n=184). CMV DNAemia was assessed using digital PCR, and a threshold of 1000 copies/mL serum was defined as reactivation; 22% of patients met this definition of CMV reactivation, however they did not have significantly worse survival than those without CMV reactivation (HR 1.5 (95% CI 0.7 - 3.0)). Monocytes that mobilize to the cancer site contribute to tumor-associated inflammation. Therefore, we explored whether a biomarker of inflammation, CRP, modified the association of CMV reactivation and HNC patient survival. In the absence of inflammation, there was no association between CMV reactivation and patient survival (HR 0.90 (95% CI 0.30 - 2.71)). However, those with both CMV reactivation and high inflammation had dramatically worse survival (HR 8.86 (95% CI 3.63 - 21.64)). These data are consistent with the recent report that CMV infected monocytes are immunosuppressive and suggest that stimulation of these monocytes to the tumor site may negatively impact patient survival. Future work should address the generalizability of this finding to other cancer types and determine whether CMV infected myeloid cells are present in the tumor microenvironment. Citation Format: Heather H. Nelson, Jeffrey S. Miller, DeVon Hunter-Schlichting, Rondi A. Butler, Karl T. Kelsey. Cytomegalovirus (CMV) reactivation and patient survival in head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 614.

Tumor-derived exosomes promote carcinogenesis of murine oral squamous cell carcinoma.

Circulating tumor-derived exosomes (TEX) interact with a variety of cells in cancer-bearing hosts, leading to cellular reprogramming which promotes disease progression. To study TEX effects on the development of solid tumors, immunosuppressive exosomes carrying PD-L1 and FasL were isolated from supernatants of murine or human HNSCC cell lines. TEX were delivered (IV) to immunocompetent C57BL/6 mice bearing premalignant oral/esophageal lesions induced by the carcinogen, 4-nitroquinoline 1-oxide (4NQO). Progression of the premalignant oropharyngeal lesions to malignant tumors was monitored. A single TEX injection increased the number of developing tumors (6.2 versus 3.2 in control mice injected with phosphate-buffered saline; P < 0.0002) and overall tumor burden per mouse (P < 0.037). The numbers of CD4+ and CD8+ T lymphocytes infiltrating the developing tumors were coordinately reduced (P < 0.01) in mice injected with SCCVII-derived TEX relative to controls. Notably, TEX isolated from mouse or human tumors had similar effects on tumor development and immune cells. A single IV injection of TEX was sufficient to condition mice harboring premalignant OSCC lesions for accelerated tumor progression in concert with reduced immune cell migration to the tumor.