Differential tumor and normal mucosa biomarker modulation by epidermal growth factor receptor (EGFR) inhibition using erlotinib in oral cavity squamous cell carcinoma (OCSCC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 6077-6077
Author(s):  
C. Tsien ◽  
M. Nyati ◽  
D. Chepeha ◽  
F. Worden ◽  
J. Helman ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Surgical Resection ◽  
Locally Advanced ◽  
Immunohistochemical Analysis ◽  
Normal Mucosa ◽  
Preclinical Model ◽  
Published Data ◽  
Head Neck Cancer ◽  
Egfr Inhibition ◽  
Tumor Biopsies

6077 Background: Targeted therapy may improve the therapeutic index in locally advanced head neck cancer if differential EGFR inhibition in tumors compared to the normal mucosa is demonstrated. Based on prior published data, EGFR degradation is an important biomarker of cytotoxicity in a preclinical model. The aim of this pilot study was to determine if there are differences in biomarker modulation between tumor and the normal mucosa and confirm our initial preclinical findings regarding EGFR degradation. Methods: Patients with primary OCSCC requiring surgical resection had normal mucosa and tumor biopsies prior to a test course of erlotinib. Patients received one week of erlotinib 150 mg qd. Repeat tumor and normal mucosal biopsies were obtained at the time of surgical resection to evaluate the effect of the EGFR inhibitor on both tumor and the normal mucosa. Changes in known preclinical markers of EGFR activity (phospho, total EGFR, AKT, STAT3) were measured by immunoblotting assays. In addition, changes in distribution of these biomarkers were analyzed by immunohistochemical analysis. Results: 12 pts were enrolled; 7 pts with paired tumor and normal mucosa biopsies. Tumor specimens showed over-expression of EGFR compared to the normal mucosa (p = 0.005). Erlotinib treatment led to marked inhibition of both pEGFR and EGFR protein (p = 0.004 and p = 0.007, respectively) in tumor biopsies. In contrast, we found heterogeneity in EGFR inhibition in the normal mucosa following erlotinib. (p = 0.1 [pEGFR], and p = 0.07 [EGFR)]) We noted dramatic reduced levels of pSrc and pSTAT3 following erlotinib in tumors compared to untreated matched tumor samples. In addition, levels of p27 were enhanced. Conclusions: Differential EGFR inhibition in tumors compared to the normal mucosa, may suggest that the addition of EGFR inhibitors to chemo-RT or accelerated RT, whose dose limiting toxicity is acute mucositis, may select patients who will benefit from targeted therapy. Our results demonstrate that EGFR inhibition by erlotinib led to marked reduction in EGFR protein levels. EGFR degradation may be an important biomarker in selecting patients predicted to have a response to TKI. These results need further validation. No significant financial relationships to disclose.

Thymoma: From Chemotherapy to Targeted Therapy

2012 ◽  
pp. 475-479
Author(s):  
Nicolas Girard
Keyword(s):  
Targeted Therapy ◽  
Personalized Medicine ◽  
Molecular Characterization ◽  
Surgical Resection ◽  
Locally Advanced ◽  
Tumor Burden ◽  
Advanced Tumor ◽  
Druggable Targets ◽  
Locally Advanced Tumor

Overview: Thymic malignancies are rare epithelial tumors that may be aggressive and difficult to treat. Thymomas are frequently eligible for upfront surgical resection. However, nearly 30% of patients present with locally advanced tumor at time of diagnosis, and chemotherapy is then used to reduce the tumor burden—possibly allowing subsequent surgery and/or radiotherapy. Metastatic and recurrent thymic malignancies may be similarly treated with chemotherapy. More recently, the molecular characterization of thymoma led to the identification of potentially druggable targets, laying the foundation to implement personalized medicine for patients.

scholarly journals A Novel Steroidogenic Factor-1 Antagonist, OR-449, as a Targeted Therapy for Adrenocortical Cancer

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A1010-A1010
Author(s):  
Paul Crowe ◽  
Ray Fox ◽  
Haiyan Tao ◽  
Emily Eastwood ◽  
Neil Raheja ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Surgical Resection ◽  
Locally Advanced ◽  
Unmet Need ◽  
Primary Treatment ◽  
Tumor Xenograft ◽  
Orphan Nuclear Receptor ◽  
Adrenocortical Cancer ◽  
Steroidogenic Factor 1 ◽  
Immunocompromised Mice

Abstract Adrenocortical carcinoma (ACC) is a rare cancer with an annual incidence of 0.7-2.0 cases per million in the US and EU. Surgical resection combined with adjuvant chemotherapy remains the primary treatment for patients with advanced disease. Although surgery is an option for most patients, oftentimes cases presenting with locally advanced or metastatic disease are not candidates for surgical resection. Furthermore, the non-specific adrenolytic and highly toxic FDA-approved chemotherapy drug, mitotane, is only marginally effective in adult and pediatric ACC. Steroidogenic factor-1 (SF-1 or NR5A1), an orphan nuclear receptor that is essential for the growth and development of the adrenal gland, is highly expressed in adult and pediatric ACC. Moreover, SF- is the major, active transcription factor in ACC (1,2). To address the unmet need for a targeted therapy in ACC, we identified potent small molecule SF-1 antagonists that block SF-1 transcriptional activity through the SF-1 ligand-binding domain (IC50 = 15-20 nM in a CHO cell reporter assay). In short-term dissociated cell cultures established from SJ-ACC3 (3), a pediatric ACC patient-derived tumor xenograft (PDX), OR-449 and a related SF-1 antagonist, OR-907S, blocked DNA synthesis as measured by inhibition of EdU incorporation in SF-1+ cells (IC50 = 500-600 nM, >80% efficacy at 10 μM) whereas OR-907R, the 100-fold less potent enantiomer of OR-907S, is nearly inactive. OR-449, which has >20% oral bioavailability and a long plasma half-life (> 9 h) in mouse, rat and dog, inhibited growth of SJ-ACC3 tumors grown in immunocompromised mice following daily oral dosing (30 mg/kg) for 4 weeks. SF-1-responsive genes, both down- and up-regulated, identified by RNAseq (by comparison of OR-907S and OR-907R in SJ-ACC3 dissociated cell culture), also responded to OR-449 in SJ-ACC3 xenografts following 7 days of dosing, indicating transcriptional regulation of SF-1 by OR-449. Importantly, in an exploratory 2-week mouse safety study, OR-449 showed no adverse effects when dosed up to 100 mg/kg. Taken together, these findings suggest that SF-1 antagonists could provide a safe and effective targeted therapy for ACC. References: (1) Mohan, et al., Curr. Opin. Endocrinol. Metab. Res., 2019; 8:72; (2) Corces, et al., Science, 2018; 362:eaav1898; (3) Pinto, et al., Clin. Cancer. Res., 2013; 19:1740.

scholarly journals EUS-FNA Biopsies to Guide Precision Medicine in Pancreatic Cancer: Results of a Pilot Study to Identify KRAS Wild-Type Tumours for Targeted Therapy

2021 ◽  
Vol 11 ◽  
Author(s):  
Joanne Lundy ◽  
Marion Harris ◽  
John Zalcberg ◽  
Allan Zimet ◽  
David Goldstein ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Targeted Therapy ◽  
Pilot Study ◽  
Precision Medicine ◽  
Molecular Analysis ◽  
Single Agent ◽  
Locally Advanced ◽  
Disease Stage ◽  
Wild Type ◽  
Egfr Inhibition

BackgroundPancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer death and lacks effective treatment options. Diagnostic endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) biopsies represent an appealing source of material for molecular analysis to inform targeted therapy, as they are often the only available tissue for patients presenting with PDAC irrespective of disease stage. However, EUS-FNA biopsies are typically not used to screen for precision medicine studies due to concerns about low tissue yield and quality. Epidermal growth factor receptor (EGFR) inhibition has shown promise in clinical trials of unselected patients with advanced pancreatic cancer, but has not been prospectively tested in KRAS wild-type patients. Here, we examine the clinical utility of EUS-FNA biopsies for molecular screening of KRAS wild-type PDAC patients for targeted anti-EGFR therapy to assess the feasibility of this approach.Patients and MethodsFresh frozen EUS-FNA or surgical biopsies from PDAC patient tumours were used to screen for KRAS mutations. Eligible patients with recurrent, locally advanced, or metastatic KRAS wild-type status who had received at least one prior line of chemotherapy were enrolled in a pilot study (ACTRN12617000540314) and treated with panitumumab at 6mg/kg intravenously every 2 weeks until progression or unacceptable toxicity. The primary endpoint was 4-month progression-free survival (PFS).Results275 patient biopsies were screened for KRAS mutations, which were detected in 88.3% of patient samples. 8 eligible KRAS wild-type patients were enrolled onto the interventional study between November 2017 and December 2020 and treated with panitumumab. 4-month PFS was 14.3% with no objective tumour responses observed. The only grade 3/4 treatment related toxicity observed was hypomagnesaemia.ConclusionsThis study demonstrates proof-of-principle feasibility to molecularly screen patients with pancreatic cancer for targeted therapies, and confirms diagnostic EUS-FNA biopsies as a reliable source of tumour material for molecular analysis. Single agent panitumumab was safe and tolerable but led to no objective tumour responses in this population.

Is Locally Advanced Head-Neck Cancer One More Candidate for Accelerated Hypofractionation?

2021 ◽  
Vol 41 (1) ◽  
pp. 467-475
Author(s):  
IOANNIS M. KOUKOURAKIS ◽  
ANNA ZYGOGIANNI ◽  
VASSILIOS KOULOULIAS ◽  
GEORGE KYRGIAS ◽  
MARIANTHI PANTELIADOU ◽  
...  
Keyword(s):  
Neck Cancer ◽  
Locally Advanced ◽  
Head Neck Cancer ◽  
Advanced Head ◽  
Head Neck

scholarly journals Co-Clinical Trials: An Innovative Drug Development Platform for Cholangiocarcinoma

2021 ◽  
Vol 14 (1) ◽  
pp. 51
Author(s):  
Brinda Balasubramanian ◽  
Simran Venkatraman ◽  
Kyaw Zwar Myint ◽  
Tavan Janvilisri ◽  
Kanokpan Wongprasert ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Targeted Therapy ◽  
Drug Development ◽  
Surgical Resection ◽  
Treatment Options ◽  
Standard Of Care ◽  
Time Data ◽  
Current Standard ◽  
Innovative Drug ◽  
Curative Intent

Cholangiocarcinoma (CCA), a group of malignancies that originate from the biliary tract, is associated with a high mortality rate and a concerning increase in worldwide incidence. In Thailand, where the incidence of CCA is the highest, the socioeconomic burden is severe. Yet, treatment options are limited, with surgical resection being the only form of treatment with curative intent. The current standard-of-care remains adjuvant and palliative chemotherapy which is ineffective in most patients. The overall survival rate is dismal, even after surgical resection and the tumor heterogeneity further complicates treatment. Together, this makes CCA a significant burden in Southeast Asia. For effective management of CCA, treatment must be tailored to each patient, individually, for which an assortment of targeted therapies must be available. Despite the increasing numbers of clinical studies in CCA, targeted therapy drugs rarely get approved for clinical use. In this review, we discuss the shortcomings of the conventional clinical trial process and propose the implementation of a novel concept, co-clinical trials to expedite drug development for CCA patients. In co-clinical trials, the preclinical studies and clinical trials are conducted simultaneously, thus enabling real-time data integration to accurately stratify and customize treatment for patients, individually. Hence, co-clinical trials are expected to improve the outcomes of clinical trials and consequently, encourage the approval of targeted therapy drugs. The increased availability of targeted therapy drugs for treatment is expected to facilitate the application of precision medicine in CCA.

scholarly journals Transcriptomic Analysis of a Diabetic Skin-Humanized Mouse Model Dissects Molecular Pathways Underlying the Delayed Wound Healing Response

Genes ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 47
Author(s):  
Carlos León ◽  
Francisco García-García ◽  
Sara Llames ◽  
Eva García-Pérez ◽  
Marta Carretero ◽  
...  
Keyword(s):  
Wound Healing ◽  
Functional Enrichment ◽  
Preclinical Model ◽  
Published Data ◽  
Diabetic Patients ◽  
Ulcer Formation ◽  
Histological Features ◽  
Depth Analysis ◽  
Wound Healing Model ◽  
Healing Model

Defective healing leading to cutaneous ulcer formation is one of the most feared complications of diabetes due to its consequences on patients’ quality of life and on the healthcare system. A more in-depth analysis of the underlying molecular pathophysiology is required to develop effective healing-promoting therapies for those patients. Major architectural and functional differences with human epidermis limit extrapolation of results coming from rodents and other small mammal-healing models. Therefore, the search for reliable humanized models has become mandatory. Previously, we developed a diabetes-induced delayed humanized wound healing model that faithfully recapitulated the major histological features of such skin repair-deficient condition. Herein, we present the results of a transcriptomic and functional enrichment analysis followed by a mechanistic analysis performed in such humanized wound healing model. The deregulation of genes implicated in functions such as angiogenesis, apoptosis, and inflammatory signaling processes were evidenced, confirming published data in diabetic patients that in fact might also underlie some of the histological features previously reported in the delayed skin-humanized healing model. Altogether, these molecular findings support the utility of such preclinical model as a valuable tool to gain insight into the molecular basis of the delayed diabetic healing with potential impact in the translational medicine field.

scholarly journals HER2-Positive Neuroendocrine Breast Cancer: Case Report and Review of Literature

Breast Care ◽  
2016 ◽  
Vol 11 (6) ◽  
pp. 424-426 ◽  
Author(s):  
Arpine Gevorgyan ◽  
Giacomo Bregni ◽  
Giulia Galli ◽  
Elisa Zanardi ◽  
Filippo de Braud ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Case Report ◽  
Targeted Therapy ◽  
Neuroendocrine Carcinoma ◽  
Immunohistochemical Analysis ◽  
Breast Cancer Case ◽  
Cancer Case ◽  
Review Of Literature ◽  
Her2 Amplification ◽  
Her2 Positive

Background: Neuroendocrine carcinoma is an uncommon histology for breast cancer. Case Report: Our patient underwent right quadrantectomy for a neuroendocrine carcinoma in 1984 and had a bone relapse 30 years later. After thorough pathological and immunohistochemical analysis the diagnosis was confirmed and HER2 amplification was observed. Here we discuss the management, rationale and results of HER2-targeted therapy in advanced neuroendocrine breast carcinoma.

scholarly journals Postoperative Radiotherapy in Head and Neck Cancer

2010 ◽  
Vol 2 (1) ◽  
pp. 43-51
Author(s):  
Vedang Murthy ◽  
Sayan Kundu ◽  
Tanweer Shahid ◽  
Ashwini Budrukkar ◽  
Tejpal Gupta ◽  
...  
Keyword(s):  
Head And Neck Cancer ◽  
Targeted Therapy ◽  
Head And Neck ◽  
Neck Cancer ◽  
Early Stage ◽  
Postoperative Radiotherapy ◽  
Locally Advanced ◽  
Head And Neck Cancers ◽  
Advanced Head ◽  
Locoregional Failure

Abstract Though early stage head and neck cancers can be cured either by surgery or radiation, patients with locally advanced disease continues to pose a therapeutic challenge. Locoregional failure is the major cause of death in head and neck cancers. As the outcome of locally advanced head and neck cancer is less than promising, a combined modality approach is generally undertaken in this group of patients. The combination of surgery, radiation and more recently, chemotherapy and targeted therapy can improve outcomes in locally advanced head and neck cancer patients. This overview discusses the rationale and role of postoperative radiotherapy (PORT) in advanced head and neck cancers, the radiotherapy technique in brief and methods of enhancing the efficacy of postoperative RT by altering the fractionation schedules and adding chemotherapy and targeted therapy.

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