scholarly journals ALK Rearrangement–Positive Pancreatic Cancer with Brain Metastasis Has Remarkable Response to ALK Inhibitors: A Case Report

2021 ◽  
Vol 11 ◽  
Author(s):  
Kai Ou ◽  
Xiu Liu ◽  
Weihua Li ◽  
Yi Yang ◽  
Jianming Ying ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Poor Prognosis ◽  
Clinical Observation ◽  
Treatment Options ◽  
Molecular Profiling ◽  
Wild Type ◽  
Alk Rearrangement ◽  
Prior Chemotherapy ◽  
Alk Inhibitors ◽  
Limited Effectiveness

Patients with metastatic pancreatic cancer typically have poor prognosis due to the limited effectiveness of existing treatment options. ALK rearrangement–positive is rare in pancreatic cancer, but may occur in those with KRAS-wild type. We present a 34-year-old young man with ALK rearrangement–positive and KRAS-wild pancreatic cancer who had a remarkable response to crizotinib after resistance to prior chemotherapy and re-response to alectinib after brain metastases developed. This clinical observation suggests that comprehensive molecular profiling to guide targeted therapies is not only feasible, but also significantly improves survival outcomes for a subgroup of patients with pancreatic cancer.

scholarly journals Oncogenic KRAS engages an RSK1/NF1 pathway to inhibit wild-type RAS signaling in pancreatic cancer

2021 ◽  
Vol 118 (21) ◽  
pp. e2016904118
Author(s):  
Derek K. Cheng ◽  
Tobiloba E. Oni ◽  
Jennifer S. Thalappillil ◽  
Youngkyu Park ◽  
Hsiu-Chi Ting ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Clinical Success ◽  
Treatment Options ◽  
Mass Spectrometry Analysis ◽  
Ductal Adenocarcinoma ◽  
Ras Signaling ◽  
Wild Type ◽  
Feedback Mechanisms ◽  
Spectrometry Analysis ◽  
Pancreatic Cancer Cells

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with limited treatment options. Although activating mutations of the KRAS GTPase are the predominant dependency present in >90% of PDAC patients, targeting KRAS mutants directly has been challenging in PDAC. Similarly, strategies targeting known KRAS downstream effectors have had limited clinical success due to feedback mechanisms, alternate pathways, and dose-limiting toxicities in normal tissues. Therefore, identifying additional functionally relevant KRAS interactions in PDAC may allow for a better understanding of feedback mechanisms and unveil potential therapeutic targets. Here, we used proximity labeling to identify protein interactors of active KRAS in PDAC cells. We expressed fusions of wild-type (WT) (BirA-KRAS4B), mutant (BirA-KRAS4BG12D), and nontransforming cytosolic double mutant (BirA-KRAS4BG12D/C185S) KRAS with the BirA biotin ligase in murine PDAC cells. Mass spectrometry analysis revealed that RSK1 selectively interacts with membrane-bound KRASG12D, and we demonstrate that this interaction requires NF1 and SPRED2. We find that membrane RSK1 mediates negative feedback on WT RAS signaling and impedes the proliferation of pancreatic cancer cells upon the ablation of mutant KRAS. Our findings link NF1 to the membrane-localized functions of RSK1 and highlight a role for WT RAS signaling in promoting adaptive resistance to mutant KRAS-specific inhibitors in PDAC.

scholarly journals Loss of p53 tumor suppression function drives invasion and genomic instability in models of murine pancreatic cancer

2022 ◽  
Author(s):  
Claudia Tonelli ◽  
Astrid Deschênes ◽  
Melissa A. Yao ◽  
Youngkyu Park ◽  
David A. Tuveson
Keyword(s):  
Pancreatic Cancer ◽  
Mouse Model ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Morphological Changes ◽  
Treatment Options ◽  
Intraepithelial Neoplasia ◽  
Ductal Adenocarcinoma ◽  
Wild Type

Pancreatic ductal adenocarcinoma (PDA) is a deadly disease with few treatment options. There is an urgent need to better understand the molecular mechanisms that drive disease progression, with the ultimate aim of identifying early detection markers and clinically actionable targets. To investigate the transcriptional and morphological changes associated with pancreatic cancer progression, we analyzed the KrasLSLG12D/+; Trp53LSLR172H/+; Pdx1-Cre (KPC) mouse model. We have identified an intermediate cellular event during pancreatic carcinogenesis in the KPC mouse model of PDA that is represented by a subpopulation of tumor cells that express KrasG12D, p53R172H and one allele of wild-type Trp53. In vivo, these cells represent a histological spectrum of pancreatic intraepithelial neoplasia (PanIN) and acinar-to-ductal metaplasia (ADM) and rarely proliferate. Following loss of wild-type p53, these precursor lesions undergo malignant de-differentiation and acquire invasive features. We have established matched organoid cultures of pre-invasive and invasive cells from murine PDA. Expression profiling of the organoids led to the identification of markers of the pre-invasive cancer cells in vivo and mechanisms of disease aggressiveness.

Immunotherapy in pancreatic cancer and the importance of tumour testing

2020 ◽  
Vol 13 (7) ◽  
pp. e235774
Author(s):  
Phuong Ngo ◽  
Mohamed Shanshal ◽  
Adam Rojan
Keyword(s):  
Pancreatic Cancer ◽  
Genetic Testing ◽  
Adjuvant Chemotherapy ◽  
Mismatch Repair ◽  
Poor Prognosis ◽  
Treatment Options ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Additional Treatment ◽  
Clinical Suspicion

Advanced pancreatic cancer carries a poor prognosis and has traditionally been treated with chemotherapy. However, immunotherapy has made great strides in a subset of patients depending on mismatch repair/microsatellite status. We present a patient with locally advanced pancreatic cancer treated with neoadjuvant chemotherapy followed by surgery and additional adjuvant chemotherapy whose disease progressed while on adjuvant chemotherapy. Tumour testing showed a mismatch repair mutation and high microsatellite instability, making her eligible for treatment with immunotherapy. Germline genetic testing confirmed the clinical suspicion of Lynch syndrome. She has had isolated sites of progression treated with radiation but overall has been receiving immunotherapy for more than 3 years, highlighting the importance of tumour testing as it may allow for additional treatment options and improved survival.

MGMT methylation as a prognostic factor in IDH wild type anaplastic gliomas.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 2523-2523
Author(s):  
Enrico Franceschi ◽  
Alicia Tosoni ◽  
Vincenzo Di Nunno ◽  
Antonella Mura ◽  
Sofia Asioli ◽  
...  
Keyword(s):  
Prognostic Factor ◽  
Poor Prognosis ◽  
Idh Mutation ◽  
Mgmt Methylation ◽  
Wild Type ◽  
Dismal Prognosis ◽  
Anaplastic Gliomas ◽  
Limited Effectiveness ◽  
Grade Iii

2523 Background: Anaplastic gliomas are classified according to the presence of IDH-mutation. IDH wild type (IDH wt) is associated with poor prognosis and limited effectiveness of treatments.The aim of this study was to find out if MGMT methylation represents a prognostic factor in this setting. Methods: Anaplastic gliomas are classified according to the presence of IDH-mutation. IDH wild type (IDH wt) is associated with poor prognosis and limited effectiveness of treatments.The aim of this study was to find out if MGMT methylation represents a prognostic factor in this setting. Results: The analysis included 73 pts with grade III, IDH wt (19.3%) gliomas. Median follow-up time was 69.9 months. Median age was 50 (Range: 18-75), M/F ratio was 40(54.8%)/33(45.2%).MGMT promoter was methylated in 34 pts (46.6%) and unmethylated in 39 pts (53.4%). After surgery, 9 pts (12.3%) received RT alone, 57 pts (78.1%) received both RT and CT (sequential, concomitant or both). Median survival was 26.2 months. In multivariate analysis age (HR = 1.064, 95%CI: 1.030-1.099; P < 0.001) and MGMT methylation (HR = 0.422, 95%CI: 0.210-0.848; P = 0.015) were independently associated with risk for death. Conclusions: IDH wild type confers a dismal prognosis in patients with grade III gliomas. MGMT methylation, as was demonstrated in glioblastoma, represents a prognostic factor that correlated with lower risk for death. Further studies will investigate potential correlations with treatments.

PET/CT IN THE DIAGNOSIS OF PANCREATIC CANCER: LITERATURE REVIEW

2018 ◽  
pp. 57-67
Author(s):  
P. E. Tulin ◽  
M. B. Dolgushin ◽  
D. I. Nevzorov ◽  
P. V. Kochergin ◽  
Yu. I. Patyutko
Keyword(s):  
Pancreatic Cancer ◽  
Literature Review ◽  
Pancreatic Neoplasms ◽  
Poor Prognosis ◽  
Modern Imaging ◽  
Pet Ct

Pancreatic cancer has a poor prognosis, often because most pancreatic neoplasms are found to be unresectable at diagnosis. Early staging of the tumor process can change the tactics of treatment and affect the survival of patients. The purpose of this review is to provide an overview of pancreatic cancer and the role of modern imaging in its diagnosis with an emphasis on PET/CT with a various radiopharmaceuticals.

scholarly journals Glioblastoma and MiRNAs

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1581
Author(s):  
Swalih P. Ahmed ◽  
Javier S. Castresana ◽  
Mehdi H. Shahi
Keyword(s):  
Brain Tumors ◽  
Human Body ◽  
Diagnostic Tool ◽  
Poor Prognosis ◽  
Treatment Options ◽  
Diagnosis And Treatment ◽  
Therapeutic Success ◽  
Knowing That ◽  
Almost All ◽  
Cell Signaling Pathways

Glioblastoma (GB) is one of the most common types of lethal brain tumors. Although several treatment options are available including surgery, along with adjuvant chemo and radiotherapy, the disease has a poor prognosis and patients generally die within 14 months of diagnosis. GB is chemo and radio resistant. Thus, there is a critical need for new insights into GB treatment to increase the chance of therapeutic success. This is why microRNA (miRNA) is being potentially considered in the diagnosis and treatment of glioblastoma. The objective of our review is to provide a holistic picture of GB up-regulated and down-regulated miRNA, in relationship with the expression of other genes, cell signaling pathways, and their role in GB diagnosis and treatment. MiRNA treatment is being considered to be used against GB together with radiotherapy and chemotherapy. Moreover, the use of miRNA as a diagnostic tool has also begun. Knowing that miRNAs are isolated in almost all human body fluids and that there are more than 3000 miRNAs in the human genome, plus the fact that each miRNA controls hundreds of different mRNAs, there is still much study needed to explore how miRNAs relate to GB for its proliferation, progression, and inhibition.

Frailty is associated with poor prognosis after resection for pancreatic cancer

2021 ◽  
Author(s):  
Kosuke Mima ◽  
Hiromitsu Hayashi ◽  
Shigeki Nakagawa ◽  
Takashi Matsumoto ◽  
Shotaro Kinoshita ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Poor Prognosis

scholarly journals Pancreatic Cancer Exposome Profile to Aid Early Detection and Inform Prevention Strategies

2021 ◽  
Vol 10 (8) ◽  
pp. 1665
Author(s):  
Maria J. Monroy-Iglesias ◽  
Saoirse Dolly ◽  
Debashis Sarker ◽  
Kiruthikah Thillai ◽  
Mieke Van Hemelrijck ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Early Detection ◽  
Immune Responses ◽  
Inflammatory Markers ◽  
Poor Prognosis ◽  
Associated Factors ◽  
Review Of The Literature ◽  
Prevention Strategies ◽  
Factors Influencing ◽  
Detection Strategies

Pancreatic cancer (PCa) is associated with a poor prognosis and high mortality rate. The causes of PCa are not fully elucidated yet, although certain exposome factors have been identified. The exposome is defined as the sum of all environmental factors influencing the occurrence of a disease during a life span. The development of an exposome approach for PCa has the potential to discover new disease-associated factors to better understand the carcinogenesis of PCa and help with early detection strategies. Our systematic review of the literature identified several exposome factors that have been associated with PCa alone and in combination with other exposures. A potential inflammatory signature has been observed among the interaction of several exposures (i.e., smoking, alcohol consumption, diabetes mellitus, obesity, and inflammatory markers) that further increases the incidence and progression of PCa. A large number of exposures have been identified such as genetic, hormonal, microorganism infections and immune responses that warrant further investigation. Future early detection strategies should utilize this information to assess individuals’ risk for PCa.

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