Azenosertib Is a Potent and Selective WEE1 Kinase Inhibitor with Broad Antitumor Activity Across a Range of Solid Tumors.

Genomic instability and accumulation of DNA damage are hallmarks of tumor development and progression. To ensure the maintenance of genomic integrity, cells rely on a coordinated DNA damage response network that regulates cell-cycle progression, including activation of WEE1-dependent cell cycle checkpoints. If DNA damage occurs during replication, the WEE1 checkpoint is activated, thereby preventing the progression of the cell cycle.

Impact of Biomarker-Matched Therapies on Outcomes in Patients with Sarcoma Enrolled in Early-Phase Clinical Trials (SAMBA 101).

Purpose: Developing new therapeutics for any of the more than 100 sarcoma subtypes presents a challenge. After progression from standard therapies, patients with sarcoma may be referred for enrollment in early-phase trials. This study aimed to investigate whether enrollment in biomarker-matched early-phase clinical trials leads to better outcomes for patients with advanced sarcoma.

A phase 1/2a safety, pharmacokinetics, and efficacy study of the novel nucleoside analog FF-10502-01 for the treatment of advanced solid tumors.

Background: The nucleoside FF-10502-01, structurally similar to but with different biologic effects than gemcitabine, shows promising activity both alone and combined with cisplatin in preclinical gemcitabine-resistant tumor models. We conducted an open-label, single-arm, 3 + 3 first-in-human trial to explore the safety, tolerability, and antitumor activity of FF-10502-01 in patients with solid tumors.

Methods: Patients with inoperable metastatic tumors refractory to standard therapies were enrolled.

Natural History of Human Epidermal Growth Factor Receptor 2-Amplified and Human Epidermal Growth Factor Receptor 2 Wild-Type Refractory Metastatic Colorectal Cancer in US Clinical Practice.

Purpose: The molecular heterogeneity of metastatic colorectal cancer (mCRC) presents a therapeutic challenge, with few trials focused on patients with human epidermal growth factor receptor 2 amplification (HER2-Amp). Our limited understanding of real-world patterns and outcomes by HER2 status of treatment-refractory patients leaves treatment decisions with little contextual information. We conducted a retrospective cohort study to describe the natural disease history of patients with refractory mCRC using an electronic health record-derived database with oncogenomic information.

Characterization of Blood-Based Molecular Profiling in Pancreatic Adenocarcinoma.

Background: Molecular profiling is being explored in pancreatic adenocarcinoma (PDAC) as a tool to assist with early detection, prognosis, and patient selection in targeted therapy clinical trials. Due to the challenges and risks of traditional tissue biopsies in pancreatic adenocarcinoma, the utility of blood-based molecular profiling is now being explored more broadly. However, given its novelty, what value blood-based molecular profiling may provide to oncologists caring for individuals with PDAC remains unknown.

Discovery of targeted expression data for novel antibody-based and chimeric antigen receptor-based therapeutics in soft tissue sarcomas using RNA-sequencing: clinical implications.

Recent failure of phase 3 trials and paucity of druggable oncogenic drivers hamper developmental therapeutics in sarcomas. Antibody-based therapeutics, like antibody-drug conjugates (ADCs) and chimeric antigen receptor (CAR)-based therapeutics, have emerged as promising strategies for anticancer drug delivery. The efficacy of these novel therapies is highly dependent on expression of the antibody target.

Molecular Profiling Practices in Pancreatic Adenocarcinoma: Academic vs Community Physicians.

Background: Pancreatic adenocarcinoma (PDAC) is relatively rare but highly aggressive, with most patients diagnosed once they have metastatic or locally invasive disease. Molecular profiling is being explored as a tool for selecting patients for targeted therapy clinical trials and for assessing whether targeted therapies may be effective in PDAC. Whether molecular profiling is being performed at both academic and community oncology clinics has yet to be examined.

Barriers to Clinical Trial Enrollment in Patients With Pancreatic Adenocarcinoma Eligible for Early-Phase Clinical Trials.

Background: Early-phase clinical trials are critical to the advancement of cancer care, especially in patients with pancreatic ductal adenocarcinoma, given its aggressive nature and limited available therapeutic options.

Methods: A retrospective chart review of all patients with refractory or metastatic pancreatic ductal adenocarcinoma, referred to the Sarah Cannon Research Institute at HealthONE between 2014 and 2019, were reviewed. Patients who completed genomic profiling and qualified for a phase 1 trial (primarily 1a but some 1b) were identified to assess barriers to trial enrollment.

Screening for Phase 1 Clinical Trials: An Opportunity to Evaluate Psychological States and Reeducate Patients on Prognosis?

Disease progression or recurrence after a period of remission can be a challenging event for individuals seeking cancer treatment. Those referred for possible phase 1 trial enrollment are often motivated to participate in these studies with hope for a cure despite approximately 5% response rates in this setting. Addressing such commonly held misunderstandings during the initial evaluation for phase 1 trial eligibility could provide a valuable opportunity to improve physician communication by identifying signs of distress or psychiatric conditions, addressing underlying psychological biases, and encouraging adaptive coping strategies.

Dual inhibition of BRAF and mTOR in -mutant pediatric, adolescent, and young adult brain tumors.

Although BRAF inhibition has demonstrated activity in -mutated brain tumors, ultimately these cancers grow resistant to BRAF inhibitor monotherapy. Parallel activation of the phosphatidylinositol 3-kinase-mammalian target of rapamycin pathway has been implicated as a mechanism of primary and secondary resistance to BRAF inhibition. Moreover, it has been shown specifically that mTOR signaling activation occurs in BRAF-mutant brain tumors.

Histology-agnostic drug development - considering issues beyond the tissue.

With advances in tumour biology and immunology that continue to refine our understanding of cancer, therapies are now being developed to treat cancers on the basis of specific molecular alterations and markers of immune phenotypes that transcend specific tumour histologies. With the landmark approvals of pembrolizumab for the treatment of patients whose tumours have high microsatellite instability and larotrectinib and entrectinib for those harbouring NTRK fusions, a regulatory pathway has been created to facilitate the approval of histology-agnostic indications. Negative results presented in the past few years, however, highlight the intrinsic complexities faced by drug developers pursuing histology-agnostic therapeutic agents.

Drug Development in Soft Tissue Sarcomas: Novel Targets and Recent Early Phase Trial Results.

Soft tissue sarcomas are a heterogeneous group of rare malignancies with few effective standard therapies. Our understanding of the underlying biology driving tumorigenesis in these mesenchymal tumors have led to a growth in drug development for soft tissue sarcomas. This review focuses on novel targets in soft tissue sarcomas, describes early clinical trial results of drugs directed at these targets, and discusses the data surrounding the use of these compounds in clinical practice and rationale for possible future US Food and Drug Administration approvals.

Unique Aberrations in Intimal Sarcoma Identified by Next-Generation Sequencing as Potential Therapy Targets.

Intimal sarcomas are rare and histologically heterogeneous tumors, commonly arising from the pulmonary arteries. They have remained challenging to treat. Few studies in the literature study the genomics of this cancer.

Molecular Profiling of Hepatocellular Carcinoma Using Circulating Cell-Free DNA.

Purpose: Molecular profiling has been used to select patients for targeted therapy and determine prognosis. Noninvasive strategies are critical to hepatocellular carcinoma (HCC) given the challenge of obtaining liver tissue biopsies.

Experimental Design: We analyzed blood samples from 206 patients with HCC using comprehensive genomic testing (Guardant Health) of circulating tumor DNA (ctDNA).

Phase I Study of the BRAF Inhibitor Vemurafenib in Combination With the Mammalian Target of Rapamycin Inhibitor Everolimus in Patients With -Mutated Malignancies.

Purpose: Parallel activation of the phosphatidylinositol 3-kinase-mammalian target of rapamycin pathway represents a mechanism of primary and acquired resistance to BRAF-targeted therapy, but the two pathways have yet to be cotargeted in humans. We performed a phase I study to evaluate the safety and activity of the BRAF inhibitor vemurafenib in combination with the mammalian target of rapamycin inhibitor everolimus in -mutated advanced solid tumors.

Patients And Methods: We performed a 3+3 dose-escalation study with escalating doses of both oral (PO) vemurafenib administered twice a day and PO everolimus administered daily.

Phase I study of nab-paclitaxel, gemcitabine, and bevacizumab in patients with advanced cancers.

Background: We performed a phase I modified 3 + 3 dose escalation study to evaluate the safety and activity of bevacizumab plus gemcitabine and nab-paclitaxel in patients with advanced solid tumours.

Methods: Patients were given fixed dose gemcitabine plus increasing doses of nab-paclitaxel and bevacizumab. Toxicity, response, and association with VEGF polymorphism was analysed.

Co-occurring Genomic Alterations and Association With Progression-Free Survival in BRAFV600-Mutated Nonmelanoma Tumors.

BRAFV600 mutations occur in multiple nonmelanoma tumors, but no US Food and Drug Administration-approved BRAF-targeted therapies exist for these cancers. BRAF inhibitor vemurafenib was recently found to demonstrate activity across various BRAF-mutated nonmelanoma cancer types. However, most tumors ultimately become resistant to BRAF-targeted monotherapy.

Clinical genomic profiling to identify actionable alterations for investigational therapies in patients with diverse sarcomas.

Background: There are currently no United States Food and Drug Administration approved molecularly matched therapies for sarcomas except gastrointestinal stromal tumors. Complicating this is the extreme diversity, heterogeneity, and rarity of these neoplasms. Few therapeutic options exist for relapsed and refractory sarcomas.

Management and Outcomes of HIV-Associated Primary Effusion Lymphoma: A Single Center Experience.

Background: Primary effusion lymphoma (PEL) is a rare malignancy usually associated with HIV infection. Management and outcomes are poorly understood.

Methods: The medical records of all patients diagnosed with HIV-associated PEL at our institution between 1999 and 2014 were reviewed.

Bilateral Facial Nerve Palsy in Acute B Cell Lymphoblastic Leukemia: A Case Report and Review of the Literature.

Acute lymphoblastic leukemia (ALL) is a haematological malignancy that can involve the central nervous system (CNS). Less than 10 % of patients with ALL have CNS involvement at presentation. The cranial nerve most commonly affected is cranial nerve VII although bilateral involvement is rare.

Acute fibrinous and organising pneumonia: a rare histopathological variant of chemotherapy-induced lung injury.

Bleomycin-induced lung injury is the most common chemotherapy-associated lung disease, and is linked with several histopathological patterns. Acute fibrinous and organising pneumonia (AFOP) is a relatively new and rare histological pattern of diffuse lung injury. We report the first known case of bleomycin-induced AFOP.