scholarly journals Rationale for MYC imaging and targeting in pancreatic cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Günter Schneider ◽  
Matthias Wirth ◽  
Ulrich Keller ◽  
Dieter Saur
Keyword(s):  
Pancreatic Cancer ◽  
Standard Of Care ◽  
Ductal Adenocarcinoma ◽  
Successful Implementation ◽  
Precision Oncology ◽  
Combination Therapies ◽  
Gastrointestinal Tumor ◽  
Myc Oncogene ◽  
Therapeutic Responses ◽  
Tumor Entities

AbstractThe incidence and lethality of pancreatic ductal adenocarcinoma (PDAC) will continue to increase in the next decade. For most patients, chemotherapeutic combination therapies remain the standard of care. The development and successful implementation of precision oncology in other gastrointestinal tumor entities point to opportunities also for PDAC. Therefore, markers linked to specific therapeutic responses and important subgroups of the disease are needed. The MYC oncogene is a relevant driver in PDAC and is linked to drug resistance and sensitivity. Here, we update recent insights into MYC biology in PDAC, summarize the connections between MYC and drug responses, and point to an opportunity to image MYC non-invasively. In sum, we propose MYC-associated biology as a basis for the development of concepts for precision oncology in PDAC.

scholarly journals Targeted Dual Intervention-Oriented Drug-Encapsulated (DIODE) Nanoformulations for Improved Treatment of Pancreatic Cancer

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1189
Author(s):  
Vijay Sagar Madamsetty ◽  
Krishnendu Pal ◽  
Shamit Kumar Dutta ◽  
Enfeng Wang ◽  
Debabrata Mukhopadhyay
Keyword(s):  
Pancreatic Cancer ◽  
Side Effects ◽  
Anticancer Agents ◽  
Targeted Delivery ◽  
Drug Loading ◽  
Ductal Adenocarcinoma ◽  
Combination Therapies ◽  
Term Survival ◽  
Therapeutic Benefits

Despite recent advancements, effective treatment for pancreatic ductal adenocarcinoma (PDAC) has remained elusive. The overall survival rate in PDAC patients has been dismally low due to resistance to standard therapies. In fact, the failure of monotherapies to provide long-term survival benefits in patients led to ascension of several combination therapies for PDAC treatment. However, these combination therapies provided modest survival improvements while increasing treatment-related adverse side effects. Hence, recent developments in drug delivery methods hold the potential for enhancing therapeutic benefits by offering cocktail drug loading and minimizing chemotherapy-associated side effects. Nanoformulations-aided deliveries of anticancer agents have been a success in recent years. Yet, improving the tumor-targeted delivery of drugs to PDAC remains a major hurdle. In the present paper, we developed several new tumor-targeted dual intervention-oriented drug-encapsulated (DIODE) liposomes. We successfully formulated liposomes loaded with gemcitabine (G), paclitaxel (P), erlotinib (E), XL-184 (c-Met inhibitor, X), and their combinations (GP, GE, and GX) and evaluated their in vitro and in vivo efficacies. Our novel DIODE liposomal formulations improved median survival in comparison with gemcitabine-loaded liposomes or vehicle. Our findings are suggestive of the importance of the targeted delivery for combination therapies in improving pancreatic cancer treatment.

Sequential assessments of KRAS-mutated circulating tumor DNA in longitudinal monitoring enable the prediction of prognosis and therapeutic responses in patients with pancreatic cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15712-e15712
Author(s):  
Fumiaki Watanabe ◽  
Koichi Suzuki ◽  
Sawako Tamaki ◽  
Hideki Ishikawa ◽  
Nao Kakizawa ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Resection ◽  
Predictive Biomarker ◽  
Circulating Tumor Dna ◽  
Ductal Adenocarcinoma ◽  
Monitoring Methods ◽  
Short Period ◽  
Prediction Of Prognosis ◽  
Tumor Dna ◽  
Therapeutic Responses

e15712 Background: Liquid biopsy enables the detection of circulating tumor DNA (ctDNA) levels, including KRAS-mutated ctDNA, which is considered a predictive biomarker for pancreatic cancer. This study aimed to evaluate the significance of sequential KRAS ctDNA assessments in longitudinal monitoring. Methods: A total of 422 blood samples were collected from 78 patients undergoing treatments for localized and metastatic pancreatic ductal adenocarcinoma. KRAS ctDNA levels was determined by droplet digital polymerase chain reaction. Longitudinal monitoring of KRAS ctDNA was performed to assess its significance for predicting recurrence and prognosis and evaluating therapeutic responses to chemotherapy. Results: In 39 patients who underwent surgery for potentially resectable tumors, sequential assessments of KRAS ctDNA in longitudinal monitoring was significantly associated with prognosis ( P < 0.001). In 39 patients who did not undergo surgery, sequential assessments of KRAS ctDNA was a predictive factor for prognosis ( P = 0.005). Multivariate analysis revealed that detection of KRAS ctDNA in longitudinal monitoring was the only independent prognostic factor regardless of tumor resection ( P< 0.001). Longitudinal monitoring revealed the significance of sequential assessments of KRAS ctDNA within a short period. The presence of KRAS ctDNA in sequential assessments within 1 year after surgery showed significant association with prognosis irrespective of recurrence ( P< 0.001). The presence of KRAS ctDNA in sequential assessments within 6 months was significantly correlated with therapeutic responses in the first line chemotherapy ( P< 0.001). Conclusions: Our study showed for the first time that sequential assessments of KRAS ctDNA levels within a short period enabled the prediction of prognosis and therapeutic response in patients with pancreatic cancer.

Thrombosis of the dorsal vein of the penis as first clinical presentation of pancreatic cancer metastatic to the penis

2019 ◽  
Vol 105 (6) ◽  
pp. NP43-NP47 ◽  
Author(s):  
Matteo Virdis ◽  
Cristiana Bonifacio ◽  
Tatiana Brambilla ◽  
Giovanni Capretti ◽  
Pasquale De Nittis ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Rare Event ◽  
Standard Of Care ◽  
Ductal Adenocarcinoma ◽  
Complete Replacement ◽  
Dorsal Vein ◽  
Excellent Control ◽  
Total Body ◽  
Penile Metastases ◽  
Tomography Scan

Introduction: Though metastatic disease is a common presentation of pancreatic adenocarcinoma, localization to the penis is an extremely rare event despite its abundant vascularization. Primary cancers responsible for penile metastases usually occur in prostate and rectum and are often associated with disseminated malignancy and poor prognosis. Case description: A 66-year-old man was diagnosed with adenocarcinoma of the tail of the pancreas after the onset of thrombosis of the dorsal vein of the penis; pubis ultrasound and total body computed tomography scan were negative for metastases at other sites. The patient was submitted to distal pancreatectomy with splenectomy for a pT3 N1 G4 pancreatic ductal adenocarcinoma. Three weeks after discharge, the patient returned to the outpatient clinic complaining of a painful permanent turgidity of the penis shaft. Ultrasound revealed a complete replacement of the cavernosal bodies by multiple nodular masses and a penile biopsy confirmed metastases from the primary pancreatic cancer. The patient started chemotherapy with NAB-paclitaxel and gemcitabine, with excellent control of symptoms. However, the disease progressed to bone and liver and the patient died 9 months after surgery. Conclusions: Penile localization is an extremely rare event and a standard of care has not been elaborated. Treatments are palliative and mainly aimed at pain relief and can comprise chemotherapy, radiotherapy, and surgery. Identification of venous thrombosis as an early sign of involvement could potentially offer patients an earlier diagnosis and a better treatment option.

Synergy of water soluble prodrug triptolide (minnelide) with gemcitabine and nab-paclitaxel in pancreatic cancer.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 259-259
Author(s):  
Vikas Dudeja ◽  
Shrey Modi ◽  
Bhuwan Giri ◽  
Kaustav Majumder ◽  
Sulagna Banerjee ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Animal Models ◽  
Low Dose ◽  
Standard Of Care ◽  
Malignant Ascites ◽  
Water Soluble ◽  
Ductal Adenocarcinoma ◽  
Model Combination ◽  
Orthotopic Model ◽  
Reduced Dose

259 Background: Gemcitabine with nab-paclitaxel is the standard of care for metastatic Pancreatic Ductal Adenocarcinoma (PDAC). Addition of nab-paclitaxel to gemcitabine improves the survival of patients with metastatic pancreatic cancer by only 6 weeks while increasing toxicity. Meaningful combinations that reduce the doses while improving efficacy are required. Water soluble prodrug of triptolide (Minnelide) is effective against PDAC in preclinical studies and has demonstrated activity in the ongoing phase I trial. We have evaluated the combination of low dose triptolide prodrug with lowered doses of Abraxane and gemcitabine in PDAC. Methods: Pancreatic cancer cell lines S2-013 and S2-VP10 were xenografted both subcutaneously as well as orthotopically in athymic nude mice. Efficacy of a combination of triptolide prodrug (Minnelide: 0.21mg/kg) with reduced dose of gemcitabine 100mg/kg + Abraxane 10mg/kg (~40% of the clinically effective dose) was evaluated and compared with both standard of care gemcitabine 250mg/kg + Abraxane 25mg/kg as well as reduced dose of gemcitabine + Abraxane in animal models. We also used the immunocompetent model where murine PDAC cell line KPC001 implanted subcutaneously in C57/bl6 mice. Results: In subcutaneous syngeneic model, combination of triptolide prodrug and paclitaxel significantly inhibited tumor growth (tumor volumes expressed as % of Control, Mean±SEM: triptolide prodrug: 75.4±25, paclitaxel: 50.0 ±3, triptolide prodrug + paclitaxel: 11.0 ±1). In metastasis model combination therapy markedly improved survival (median survival in days: Vehicle-13, triptolide prodrug -20, standard of care -45, reduced dose standard of care-30, and Minnelide + reduced dose standard of care (all mice alive at 90 days). Combination of triptolide prodrug and low dose gemcitabine + nab-paclitaxel decreased tumor size, increased survival, reduced metastases and malignant ascites in orthotopic model of PDAC. Conclusions: Triptolide prodrug synergizes with reduced dose standard of care (gemcitabine and nab-paclitaxel) and helps in reducing the doses of these toxic drugs all the while achieving same or better efficacy in animal models of PDAC.

scholarly journals Kallikrein-Related Peptidase 6 Is Associated with the Tumour Microenvironment of Pancreatic Ductal Adenocarcinoma

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 3969
Author(s):  
Juliana B. Candido ◽  
Oscar Maiques ◽  
Melanie Boxberg ◽  
Verena Kast ◽  
Eleonora Peerani ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Standard Of Care ◽  
Tumour Microenvironment ◽  
Ductal Adenocarcinoma ◽  
Therapeutic Approaches ◽  
Novel Treatments ◽  
Pancreatic Cancer Cells ◽  
Invasive Tumour ◽  
Mrna And Protein Expression

As cancer-associated factors, kallikrein-related peptidases (KLKs) are components of the tumour microenvironment, which represents a rich substrate repertoire, and considered attractive targets for the development of novel treatments. Standard-of-care therapy of pancreatic cancer shows unsatisfactory results, indicating the need for alternative therapeutic approaches. We aimed to investigate the expression of KLKs in pancreatic cancer and to inhibit the function of KLK6 in pancreatic cancer cells. KLK6, KLK7, KLK8, KLK10 and KLK11 were coexpressed and upregulated in tissues from pancreatic cancer patients compared to normal pancreas. Their high expression levels correlated with each other and were linked to shorter survival compared to low KLK levels. We then validated KLK6 mRNA and protein expression in patient-derived tissues and pancreatic cancer cells. Coexpression of KLK6 with KRT19, αSMA or CD68 was independent of tumour stage, while KLK6 was coexpressed with KRT19 and CD68 in the invasive tumour area. High KLK6 levels in tumour and CD68+ cells were linked to shorter survival. KLK6 inhibition reduced KLK6 mRNA expression, cell metabolic activity and KLK6 secretion and increased the secretion of other serine and aspartic lysosomal proteases. The association of high KLK levels and poor prognosis suggests that inhibiting KLKs may be a therapeutic strategy for precision medicine.

scholarly journals Morphologic and Molecular Landscape of Pancreatic Cancer Variants as the Basis of New Therapeutic Strategies for Precision Oncology

2020 ◽  
Vol 21 (22) ◽  
pp. 8841
Author(s):  
Chiara Bazzichetto ◽  
Claudio Luchini ◽  
Fabiana Conciatori ◽  
Vanja Vaccaro ◽  
Ilaria Di Cello ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Treatment Strategies ◽  
Medullary Carcinoma ◽  
Undifferentiated Carcinoma ◽  
World Health ◽  
Ductal Adenocarcinoma ◽  
Current Evidence ◽  
Precision Oncology ◽  
Tumor Type ◽  
The World

To date, pancreatic cancer is still one of the most lethal cancers in the world, mainly due to the lack of early diagnosis and personalized treatment strategies. In this context, the possibility and the opportunity of identifying genetic and molecular biomarkers are crucial to improve the feasibility of precision medicine. In 2019, the World Health Organization classified pancreatic ductal adenocarcinoma cancer (the most common pancreatic tumor type) into eight variants, according to specific histomorphological features. They are: colloid carcinoma, medullary carcinoma, adenosquamous carcinoma, undifferentiated carcinoma, including also rhabdoid carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, hepatoid carcinoma, and signet-ring/poorly cohesive cells carcinoma. Interestingly, despite the very low incidence of these variants, innovative high throughput genomic/transcriptomic techniques allowed the investigation of both somatic and germline mutations in each specific variant, paving the way for their possible classification according also to specific alterations, along with the canonical mutations of pancreatic cancer (KRAS, TP53, CDKN2A, SMAD4). In this review, we aim to report the current evidence about genetic/molecular profiles of pancreatic cancer variants, highlighting their role in therapeutic and clinical impact.

scholarly journals AMPK Is the Crucial Target for the CDK4/6 Inhibitors Mediated Therapeutic Responses in PANC-1 and MIA PaCa-2 Pancreatic Cancer Cell Lines

Stresses ◽  
2021 ◽  
Vol 1 (1) ◽  
pp. 48-68
Author(s):  
Bortecine Sevgin ◽  
Merve Nur Coban ◽  
Özge Rencuzogullari ◽  
Ajda Coker-Gurkan ◽  
Pinar Obakan-Yerlikaya ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Survival ◽  
Ductal Adenocarcinoma ◽  
Cancer Type ◽  
Dependent Manner ◽  
Ampk Signaling ◽  
Signaling Axis ◽  
A Cell ◽  
Reduce Cell Survival ◽  
Therapeutic Responses

The survival rate of pancreatic ductal adenocarcinoma (PDAC) patients is short, and PDAC is a cancer type that ranks fourth in the statistics regarding death due to cancer. Mutation in the KRAS gene, which plays a role in pancreatic cancer development, activates the PI3K/AKT/mTOR signaling pathway. The activity of the AMPK as a cellular energy sensor is one of the fundamental mechanisms that can induce effective therapeutic responses against CDK4/6 inhibitors via adjusting the cellular and tumor microenvironment stress management. The phosphorylation of AMPKα at the different phosphorylation residues such as Thr172 and Ser 377 causes metabolic differentiation in the cells following CDK4/6 inhibitor treatment in accordance with an increased cell cycle arrest and senescence under the control of different cellular players. In this study, we examined the competencies of the CDK4/6 inhibitors LY2835219 and PD-0332991 on the mechanism of cell survival and death based on AMPK signaling. Both CDK4/6 inhibitors LY2835219 and PD-0332991 modulated different molecular players on the PI3K/AKT/mTOR and AMPK signaling axis in different ways to reduce cell survival in a cell type dependent manner. These drugs are potential inducers of apoptosis and senescence that can alter the therapeutic efficacy cells.

scholarly journals The Identification of the Anthracycline Aclarubicin as an Effective Cytotoxic Agent for Pancreatic Cancer

2020 ◽  
Author(s):  
Thomas Brouwer ◽  
Sabina Y van der Zanden ◽  
Jaap DH van Eendenburg ◽  
Bert A Bonsing ◽  
Noel FCC de Miranda ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Lines ◽  
Dose Range ◽  
Standard Of Care ◽  
New Combination ◽  
Patient Treatment ◽  
Ductal Adenocarcinoma ◽  
Pdac Cell ◽  
Short Term Exposure ◽  
Low Passage

Abstract BackgroundPancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of cancer, mainly due to its delayed diagnosis and lack of effective therapeutic options. Therefore, it is imperative to find novel treatment options for PDAC. Here, we tested a series of conventional chemotherapeutics together with anthracycline compounds as single agents or in combination, determining their effectivity against established commercial and patient-derived, low passage PDAC cell lines.MethodsProliferation and colony formation assays were performed to determine the anti-cancer activity of anthracyclines; aclarubicin and doxorubicin, on commercial and patient-derived, low passage PDAC cell lines. In addition, the effect of standard of care drugs gemcitabine and individual components of FOLFIRINOX were also investigated. The assays involved short-term exposure to the drugs in order to mimic pharmacokinetics in a patient.ResultsAclarubicin showed superior anti-tumor activity compared to other anthracyclines and standard of care drugs (gemcitabine and individual components of FOLFIRINOX) in a patient-derived, low passage PDAC cell line. Importantly, the combination of gemcitabine and aclarubicin showed a synergistic effect at a dose range where the single agents by themselves were ineffective. Subsequent testing in commercial cell lines showed similar cytotoxic effects of aclarubicin in two out of three cell lines. Gemcitabine and doxorubicin had variable responses between the cell lines, but their effect never exceeded that of aclarubicin.ConclusionsAclarubicin is cytotoxic for commercial and patient-derived low-passage PDAC cell lines, at doses lower than peak serum concentrations for patient treatment. Our findings support a (re-)consideration of aclarubicin as a backbone of new combination regimens for pancreatic cancer patients.

scholarly journals The Evolving Understanding of the Molecular and Therapeutic Landscape of Pancreatic Ductal Adenocarcinoma

Diseases ◽  
2018 ◽  
Vol 6 (4) ◽  
pp. 103 ◽  
Author(s):  
Ashleigh Parkin ◽  
Jennifer Man ◽  
Angela Chou ◽  
Adnan Nagrial ◽  
Jaswinder Samra ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Treatment Strategies ◽  
Current Status ◽  
Ductal Adenocarcinoma ◽  
Molecular Heterogeneity ◽  
Precision Oncology ◽  
Molecular Stratification ◽  
Therapeutic Landscape ◽  
Genomic Fingerprint ◽  
Novel Treatment Strategies

Pancreatic cancer is the third leading cause of cancer-related deaths, characterised by poor survival, marked molecular heterogeneity and high intrinsic and acquired chemoresistance. Only 10–20% of pancreatic cancer patients present with surgically resectable disease and even then, 80% die within 5 years. Our increasing understanding of the genomic heterogeneity of cancer suggests that the failure of definitive clinical trials to demonstrate efficacy in the majority of cases is likely due to the low proportion of responsive molecular subtypes. As a consequence, novel treatment strategies to approach this disease are urgently needed. Significant developments in the field of precision oncology have led to increasing molecular stratification of cancers into subtypes, where individual cancers are selected for optimal therapy depending on their molecular or genomic fingerprint. This review provides an overview of the current status of clinically used and emerging treatment strategies, and discusses the advances in and the potential for the implementation of precision medicine in this highly lethal malignancy, for which there are currently no curative systemic therapies.

Sequence therapy in metastatic pancreatic cancer

2018 ◽  
Vol 56 (06) ◽  
pp. 578-582 ◽  
Author(s):  
Oliver Waidmann ◽  
Uwe Pelzer ◽  
Stefan Boeck ◽  
Dirk-Thomas Waldschmidt
Keyword(s):  
Pancreatic Cancer ◽  
Overall Survival ◽  
Therapeutic Option ◽  
Standard Of Care ◽  
New Combination ◽  
Metastatic Pancreatic Cancer ◽  
Second Line ◽  
Combination Therapies ◽  
First Line ◽  
Cancer Diseases

AbstractPancreatic cancer is one of the most lethal cancer diseases. For years, gemcitabine has been the standard of care and the only therapeutic option in patients with metastatic pancreatic cancer. Within the last years, new combination therapies have been established for first-line treatment, which significantly improve overall survival in comparison to gemcitabine monotherapy. Furthermore, new second-line therapies have been identified, which significantly improve overall survival. The current manuscript summarizes briefly standard of care first- and second-line chemotherapies and discusses possible treatment sequences.

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