scholarly journals Novel Use of Hypoxia-Inducible Polymerizable Protein to Augment Chemotherapy for Pancreatic Cancer

Pharmaceutics ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 128
Author(s):  
Andrew Gdowski ◽  
Hamed Hayatshahi ◽  
Rafal Fudala ◽  
Rohan Joshi ◽  
Jin Liu ◽  
...  
Keyword(s):  
Small Molecule ◽  
Pancreatic Tumor ◽  
Direct Injection ◽  
Locally Advanced ◽  
Tumor Stroma ◽  
The United States ◽  
Pancreatic Tissue ◽  
Tumor Xenograft ◽  
Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies and is the fourth leading cause of cancer-related deaths in the United States. Unfortunately, 80–85% of patients are diagnosed with unresectable, advanced stage tumors. These tumors are incurable and result in a median survival less than approximately six months and an overall 5-year survival rate of less than 7%. Whilst chemotherapy is a critical treatment, cure is not possible without surgical resection. The poor clinical outcomes in PDAC can be partially attributed to its dense desmoplastic stroma, taking up roughly 80% of the tumor mass. The stroma surrounding the tumor disrupts the normal architecture of pancreatic tissue leading to poor vascularization, high intratumoral pressure along with hypoxia and an acidic tumor microenvironment. This complicated microenvironment presents a significant challenge for drug delivery. The current manuscript discusses a novel approach to overcome many of these various obstacles. A complex of gemcitabine (GEM) and hemoglobin S (HbS) was formulated, which self-polymerizes under hypoxic and acidic conditions. When polymerized, HbS has the potential to break the tumor stroma, decrease intratumoral pressure, and therefore improve the treatment efficacy of standard therapy. Intratumoral injection of HbS with a fluorescent small molecule surrogate for GEM into a pancreatic tumor xenograft resulted in improved dissemination of the small molecule throughout the pancreatic tumor. The self-polymerization of HbS + GEM was significantly more effective than either agent individually at decreasing tumor size in an in vivo PDAC mouse model. These findings would suggest a clinical benefit from delivering the complex of GEM and HbS via direct injection by endoscopic ultrasound (EUS). With such a treatment option, patients with locally advanced disease would have the potential to become surgical candidates, offering them a chance for cure.

scholarly journals Integrin alpha 2 (Itga2), CD49b, is differentially expressed in pancreatic ductal adenocarcinoma.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
United States ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cell Adhesion Molecule ◽  
Pancreatic Tumor ◽  
The United States ◽  
Pancreatic Tissue ◽  
Ductal Adenocarcinoma ◽  
Novel Therapies ◽  
Tissue Of Origin ◽  
Level Analysis

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of death from cancer in the United States (1, 2). Novel therapies are required to extend survival in PDAC and systems-level analysis of the tumors transcriptome as compared to the tissue of origin can reveal the basic transcriptional nature of tumors and how they differ from the tissue in which they reside and from which they originate (3). In this study, we compared the transcriptome of PDAC tumors isolated from patients with PDAC as compared to healthy, non-affected pancreatic tissue using two separate datasets (4, 5). We found that the cell adhesion molecule integrin alpha 2 (Itga2), also known as CD49b, was among the genes whose expression was most significantly different between PDAC and the benign pancreas. Itga2 expression was significantly higher in PDAC tumors compared to non-affected pancreatic tissue. Pancreatic ductal adenocarcinomas increase the expression of Itga2 during the transition from benign pancreatic tissue to transformed pancreatic tumor.

scholarly journals ITGA5 inhibition in pancreatic stellate cells attenuates desmoplasia and potentiates efficacy of chemotherapy in pancreatic cancer

2019 ◽  
Vol 5 (9) ◽  
pp. eaax2770 ◽  
Author(s):  
Praneeth R. Kuninty ◽  
Ruchi Bansal ◽  
Susanna W. L. De Geus ◽  
Deby F. Mardhian ◽  
Jonas Schnittert ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Tumor Stroma ◽  
Stellate Cells ◽  
Pancreatic Stellate Cells ◽  
Ductal Adenocarcinoma ◽  
Tumor Penetration ◽  
Desmoplastic Stroma ◽  
Integrin Α5

Abundant desmoplastic stroma is the hallmark for pancreatic ductal adenocarcinoma (PDAC), which not only aggravates the tumor growth but also prevents tumor penetration of chemotherapy, leading to treatment failure. There is an unmet clinical need to develop therapeutic solutions to the tumor penetration problem. In this study, we investigated the therapeutic potential of integrin α5 (ITGA5) receptor in the PDAC stroma. ITGA5 was overexpressed in the tumor stroma from PDAC patient samples, and overexpression was inversely correlated with overall survival. In vitro, knockdown of ITGA5 inhibited differentiation of human pancreatic stellate cells (hPSCs) and reduced desmoplasia in vivo. Our novel peptidomimetic AV3 against ITGA5 inhibited hPSC activation and enhanced the antitumor effect of gemcitabine in a 3D heterospheroid model. In vivo, AV3 showed a strong reduction of desmoplasia, leading to decompression of blood vasculature, enhanced tumor perfusion, and thereby the efficacy of gemcitabine in co-injection and patient-derived xenograft tumor models.

scholarly journals A cell type-selective apoptosis-inducing small molecule for the treatment of brain cancer

2019 ◽  
Vol 116 (13) ◽  
pp. 6435-6440 ◽  
Author(s):  
Natasha C. Lucki ◽  
Genaro R. Villa ◽  
Naja Vergani ◽  
Michael J. Bollong ◽  
Brittney A. Beyer ◽  
...  
Keyword(s):  
Small Molecule ◽  
Brain Cancer ◽  
Critical Role ◽  
Tumor Formation ◽  
Tumor Xenograft ◽  
Drug Candidate ◽  
Cell Type ◽  
Caspase 1 ◽  
A Cell

Glioblastoma multiforme (GBM; grade IV astrocytoma) is the most prevalent and aggressive form of primary brain cancer. A subpopulation of multipotent cells termed GBM cancer stem cells (CSCs) play a critical role in tumor initiation, tumor maintenance, metastasis, drug resistance, and recurrence following surgery. Here we report the identification of a small molecule, termed RIPGBM, from a cell-based chemical screen that selectively induces apoptosis in multiple primary patient-derived GBM CSC cultures. The cell type-dependent selectivity of this compound appears to arise at least in part from redox-dependent formation of a proapoptotic derivative, termed cRIPGBM, in GBM CSCs. cRIPGBM induces caspase 1-dependent apoptosis by binding to receptor-interacting protein kinase 2 (RIPK2) and acting as a molecular switch, which reduces the formation of a prosurvival RIPK2/TAK1 complex and increases the formation of a proapoptotic RIPK2/caspase 1 complex. In an orthotopic intracranial GBM CSC tumor xenograft mouse model, RIPGBM was found to significantly suppress tumor formation in vivo. Our chemical genetics-based approach has identified a drug candidate and a potential drug target that provide an approach to the development of treatments for this devastating disease.

scholarly journals Organoids from the Human Fetal and Adult Pancreas

2019 ◽  
Vol 19 (12) ◽  
Author(s):  
Jeetindra R. A. Balak ◽  
Juri Juksar ◽  
Françoise Carlotti ◽  
Antonio Lo Nigro ◽  
Eelco J. P. de Koning
Keyword(s):  
Cell Biology ◽  
Cell Formation ◽  
Pancreatic Tissue ◽  
Ductal Adenocarcinoma ◽  
Disease Modelling ◽  
In Vivo Models ◽  
Pancreatic Cell ◽  
Culture Techniques

Abstract Purpose of Review Novel 3D organoid culture techniques have enabled long-term expansion of pancreatic tissue. This review comprehensively summarizes and evaluates the applications of primary tissue–derived pancreatic organoids in regenerative studies, disease modelling, and personalized medicine. Recent Findings Organoids derived from human fetal and adult pancreatic tissue have been used to study pancreas development and repair. Generated adult human pancreatic organoids harbor the capacity for clonal expansion and endocrine cell formation. In addition, organoids have been generated from human pancreatic ductal adenocarcinoma in order to study tumor behavior and assess drug responses. Summary Pancreatic organoids constitute an important translational bridge between in vitro and in vivo models, enhancing our understanding of pancreatic cell biology. Current applications for pancreatic organoid technology include studies on tissue regeneration, disease modelling, and drug screening.

scholarly journals Cancer-Associated Fibroblasts in Pancreatic Cancer: Should They Be Deleted or Reeducated?

2018 ◽  
Vol 17 (4) ◽  
pp. 1016-1019 ◽  
Author(s):  
Chao Qu ◽  
Qing Wang ◽  
Zhiqiang Meng ◽  
Peng Wang
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Progression ◽  
Cancer Biology ◽  
Tumor Stroma ◽  
Ductal Adenocarcinoma ◽  
Migration And Invasion ◽  
Therapeutic Effects ◽  
Cancer Associated Fibroblasts

Pancreatic ductal adenocarcinoma is characterized by an extensive stromal response called desmoplasia. Within the tumor stroma, cancer-associated fibroblasts (CAFs) are the primary cell type. CAFs have been shown to play a role in pancreatic cancer progression; they secrete growth factors, inflammatory cytokines, and chemokines that stimulate signaling pathways in cancer cells and modulate the cancer biology toward increased aggressiveness. Therefore, targeting CAFs may serve as a powerful weapon against pancreatic cancer and improve therapeutic effects. However, a previous study aiming to deplete CAFs by inhibiting sonic Hedgehog signaling failed to show any benefit in survival time of pancreatic cancer patients. We reported that the natural product curcumin reeducated CAFs in pancreatic cancer treatment. A low concentration of curcumin reversed the activation of fibroblasts without exhibiting growth suppression effects. In addition, curcumin suppressed CAF-induced pancreatic cancer cell migration and invasion in vitro and lung metastasis in vivo. The results of our study suggest that active CAFs can be inactivated by certain natural products such as curcumin. Reeducation of CAFs back to their normal state, rather than their indiscriminate depletion, may broaden our view in the development of therapeutic options for the treatment of pancreatic cancer.

scholarly journals A First-In-Class, Humanized Antibody Targeting Alternatively Spliced Tissue Factor: Preclinical Evaluation in an Orthotopic Model of Pancreatic Ductal Adenocarcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Clayton S. Lewis ◽  
Aniruddha Karve ◽  
Kateryna Matiash ◽  
Timothy Stone ◽  
Jingxing Li ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Tissue Factor ◽  
Tumor Tissue ◽  
Single Agent ◽  
The United States ◽  
Ductal Adenocarcinoma ◽  
Boyden Chamber ◽  
Orthotopic Model ◽  
Alternatively Spliced

In 2021, pancreatic ductal adenocarcinoma (PDAC) is the 3rd leading cause of cancer deaths in the United States. This is largely due to a lack of symptoms and limited treatment options, which extend survival by only a few weeks. There is thus an urgent need to develop new therapies effective against PDAC. Previously, we have shown that the growth of PDAC cells is suppressed when they are co-implanted with RabMab1, a rabbit monoclonal antibody specific for human alternatively spliced tissue factor (asTF). Here, we report on humanization of RabMab1, evaluation of its binding characteristics, and assessment of its in vivo properties. hRabMab1 binds asTF with a KD in the picomolar range; suppresses the migration of high-grade Pt45.P1 cells in Boyden chamber assays; has a long half-life in circulation (~ 5 weeks); and significantly slows the growth of pre-formed orthotopic Pt45.P1 tumors in athymic nude mice when administered intravenously. Immunohistochemical analysis of tumor tissue demonstrates the suppression of i) PDAC cell proliferation, ii) macrophage infiltration, and iii) neovascularization, whereas RNAseq analysis of tumor tissue reveals the suppression of pathways that promote cell division and focal adhesion. This is the first proof-of-concept study whereby a novel biologic targeting asTF has been investigated as a systemically administered single agent, with encouraging results. Given that hRabMab1 has a favorable PK profile and is able to suppress the growth of human PDAC cells in vivo, it comprises a promising candidate for further clinical development.

Morphological and biochemical heterogeneity in the tissue of pancreatic ductal adenocarcinoma (PDAC) according to structural and spectrometric MRI data.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16727-e16727
Author(s):  
Dmitry Ya. Iozefi ◽  
Mikhail A. Vinidchenko ◽  
Nikolay S. Demchenko ◽  
Oleg I. Kit ◽  
Yuriy A. Fomenko ◽  
...  
Keyword(s):  
Chronic Pancreatitis ◽  
Lactate Concentration ◽  
Small Region ◽  
Pancreatic Tissue ◽  
Small Sample ◽  
Ductal Adenocarcinoma ◽  
Diagnostic Model ◽  
Lipid Concentration ◽  
Dixon Method

e16727 Background: Comparing the MRI characteristics of pancreatic tissue in normal, solid adenocarcinomas and chronic pancreatitis in a multiparametric study, the radiologist needs tools that reduce the subjective component in making a diagnostic decision. The study is devoted to the assessment of structural heterogeneity, diffusion coefficient, lipid and lactate concentration according to MR spectroscopy in vivo. PDAС cells are proliferating and surviving within a particularly severe microenvironment characterized by relative hypovascularity, hypoxia, and nutrient deprivation. In this case cells have to show biochemical flexibility (survival phenotype) in order to adapt to unusual conditions. Methods: 20 patients with pancreatic adenocarcinomas (PDAC), 10 patients with chronic pancreatitis and 10 patients with unchanged pancreas were examined MRI using Signa HD 1.5 t General Electric. The results of their multiparametric imaging and NMR spectroscopy were investigated and compared.The heterogeneity coefficients (HC) were measured as ratio standard deviation in small region of interest to signal intensity in T1FS and T2. Lipid concentration was measured by Dixon method as the pancreatic -to-splenic attenuation ratio. Results: In a small sample, we observed a significant increase in HC in chronic pancreatitis, and in solid tissue in adenocarcinomas in comparison with normal tissue, depending on the main source of the MR signal (hydrogen in the macromolecules or hydrogen of water and fat). In adenocarcinomas, an increase in the signal from lipids (lip13a) peak was revealed, with a decrease in the total lipid concentration. A decrease in lipid concentration in the tumor in the presence of diffusion restriction (ADC 0,001-0,0016 мм2/s) and the appearance of a peak of lactate may be a biochemical marker of adenocarcinoma. In chronic pancreatitis, an increase in the mass fraction of lipids was revealed. Conclusions: The results obtained in current and future in-depth studies are promising for creation of a metabolically oriented diagnostic model of pancreatic cancer.

241 Small Molecule Inhibitors Xmd8-92 and Pv1019 Inhibit Pancreatic Tumor Xenograft Growth via a DCLK1 Dependent Mechanism

2013 ◽  
Vol 144 (5) ◽  
pp. S-53
Author(s):  
Sripathi M. Sureban ◽  
Dongfeng Qu ◽  
Parthasarathy Chandrakesan ◽  
Randal May ◽  
Nathaniel Weygant ◽  
...  
Keyword(s):  
Small Molecule ◽  
Pancreatic Tumor ◽  
Small Molecule Inhibitors ◽  
Tumor Xenograft ◽  
Xenograft Growth ◽  
Tumor Xenograft Growth ◽  
Dependent Mechanism

scholarly journals DFMO Improves Survival and Increases Immune Cell Infiltration in Association with MYC Downregulation in the Pancreatic Tumor Microenvironment

2021 ◽  
Vol 22 (24) ◽  
pp. 13175
Author(s):  
Sai Preethi Nakkina ◽  
Sarah B. Gitto ◽  
Jordan M. Beardsley ◽  
Veethika Pandey ◽  
Michael W. Rohr ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Immune Suppression ◽  
Pancreatic Tumor ◽  
Immune Cell ◽  
Innate Immune ◽  
Ductal Adenocarcinoma ◽  
Tumor Infiltration ◽  
Effective Treatment Modality

Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor five-year survival rate of less than 10%. Immune suppression along with chemoresistance are obstacles for PDAC therapeutic treatment. Innate immune cells, such as tumor-associated macrophages, are recruited to the inflammatory environment of PDAC and adversely suppress cytotoxic T lymphocytes. KRAS and MYC are important oncogenes associated with immune suppression and pose a challenge to successful therapies. Here, we targeted KRAS, through inhibition of downstream c-RAF with GW5074, and MYC expression via difluoromethylornithine (DFMO). DFMO alone and with GW5074 reduced in vitro PDAC cell viability. Both DFMO and GW5074 showed efficacy in reducing in vivo PDAC growth in an immunocompromised model. Results in immunocompetent syngeneic tumor-bearing mice showed that DFMO and combination treatment markedly decreased tumor size, but only DFMO increased survival in mice. To further investigate, immunohistochemical staining showed DFMO diminished MYC expression and increased tumor infiltration of macrophages, CD86+ cells, CD4+ and CD8+ T lymphocytes. GW5074 was not as effective in modulating the tumor infiltration of total CD3+ lymphocytes or tumor progression and maintained MYC expression. Collectively, this study highlights that in contrast to GW5074, the inhibition of MYC through DFMO may be an effective treatment modality to modulate PDAC immunosuppression.

scholarly journals NetrinG1+ cancer-associated fibroblasts generate unique extracellular vesicles that support the survival of pancreatic cancer cells under nutritional stress

2021 ◽  
Author(s):  
Kristopher S Raghavan ◽  
Ralph Francescone ◽  
Janusz Franco-Barraza ◽  
Jaye C Gardiner ◽  
Débora B Vendramini-Costa ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Extracellular Vesicles ◽  
Tumor Stroma ◽  
The United States ◽  
Ductal Adenocarcinoma ◽  
Dependent Manner ◽  
Cancer Associated Fibroblasts ◽  
Fibrous Stroma ◽  
Pancreatic Cancer Cells ◽  
Α5β1 Integrin

It is projected that, in 5 years, pancreatic cancer will become the second deadliest cancer in the United States. A unique aspect of pancreatic ductal adenocarcinoma (PDAC) is its stroma; rich in cancer-associated fibroblasts (CAFs) and a dense CAF-generated extracellular matrix (ECM). This fibrous stroma, known as desmoplasia, causes the collapse of local blood vessels rendering a nutrient-deprived milieu. Hence, PDAC cells are nurtured by local CAF-secreted products, which include, among others, CAF-generated small extracellular vesicles (sEVs). It is well-accepted that upon culturing functionally tumor-promoting CAFs under pathophysiological-relevant conditions (e.g., within self-produced ECM), these cells express NetrinG1 (NetG1) and sustain endosomal pools rich in active α5β1-integrin, traits indicative of poor patient survival. We herein report that NetG1+ CAFs generate sEVs that rescue PDAC cells from nutrient-deprived induced apoptosis. Two unique sEVs, NetG1+ and α5β1-integrin+, were uncovered. The former constitutes cargo of CAF-generated exomeres, and the latter is detected in classic exosomes. Proteomic and metabolomic analyses showed that the sEV-dependent PDAC survival is, at least in part, dictated by the cargo packaged within sEVs in a NetG1-dependent manner. Indeed, despite producing a similar number of vesicles, selected key proteins and metabolites (e.g., glutamine) were incorporated within the unique sEVs. Finally, we found that NetG1 and α5β1-integrin were detected in sEVs collected from plasma of PDAC patients, while their concomitant levels were significantly lower in plasma of sex/age-matched healthy donors. The discovery of these tumor-supporting CAF sEVs opens a new investigative avenue in tumor-stroma interactions and stroma staging detection.

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