facilitating-repeat-intracarotid-injections-mouse-models-novel

Facilitating Repeat Intracarotid Injections in Mouse Models by a Novel Injection Site Repair Technique

Given recent advances in the delivery of novel antitumor therapeutics using endovascular selective intraarterial delivery methods in neuro-oncology, there ...

The University of Texas MD Anderson Cancer Center

Despite significant improvement in understanding of molecular underpinnings driving glioblastoma, there is minimal improvement in overall survival of patients. This poor outcome is caused in part by traditional designs of early phase clinical trials, which focus on clinical assessments of drug toxicity and response. Window of opportunity trials overcome this shortcoming by assessing drug-induced on-target molecular alterations in post-treatment human tumor specimens. This article provides an overview of window of opportunity trials, including novel designs for incorporating biologic end points into early stage trials in context of brain tumors, and examples of successfully executed window of opportunity trials for glioblastoma.

Window of Opportunity Clinical Trials to Evaluate Novel Therapies for Brain Tumors.

Fusion genes form as a result of abnormal chromosomal rearrangements linking previously separate genes into one transcript. The FGFR3-TACC3 fusion gene (F3-T3) has been shown to drive gliomagenesis in glioblastoma (GBM), a cancer that is notoriously resistant to therapy. However, successful targeting of F3-T3 via small molecular inhibitors has not revealed robust therapeutic responses, and specific targeting of F3-T3 has not been achieved heretofore. Here, we demonstrate that depleting F3-T3 using custom siRNA to the fusion breakpoint junction results in successful inhibition of F3-T3+ GBMs, and that exosomes can successfully deliver these siRNAs.

RNAi technology targeting the  fusion breakpoint: an opportunity for precision medicine.

Delta-24-based oncolytic viruses are conditional replication adenoviruses developed to selectively infect and replicate in retinoblastoma 1 (Rb)-deficient cancer cells but not normal cell with intact Rb1 pathways. Over the years, there has been a significant evolution in the design of Delta-24 based on a better understanding of the underlying basis for infection, replication, and spread within cancer. One example is the development of Delta-24-RGD (DNX-2401), where the arginine-glycine-aspartate (RGD) domain enhances the infectivity of Delta-24 for cancer cells. DNX-2401 demonstrated objective biological and clinical responses during a phase I window of opportunity clinical trial for recurrent human glioblastoma. In long-term responders (> 3 years), there was evidence of immune infiltration (T cells and macrophages) into the tumor microenvironment with minimal toxicity. Although more in-depth analysis and phase III studies are pending, these results indicate that Delta-24-based adenovirus therapy may induce an antitumor response in glioblastoma, resulting in long-term antitumor immune response. In this review, the authors discuss the preclinical and clinical development of Delta-24 oncolytic adenoviral therapy for glioblastoma and describe structural improvements to Delta-24 that have enhanced its efficacy in vivo. They also highlight ongoing research that attempts to address the remaining obstacles limiting efficacy of Delta-24 adenovirus therapy for glioblastoma.

Delta-24 adenoviral therapy for glioblastoma: evolution from the bench to bedside and future considerations.

Survival for glioblastoma remains very poor despite decades of research, with a 5-year survival of only 5%. The technological improvements that have revolutionized treatment of ischemic stroke and brain aneurysms have great potential in providing more precise and selective delivery of cancer therapeutic agents to brain tumors.

Perfusion-guided endovascular super-selective intra-arterial infusion for treatment of malignant brain tumors.

Polynucleotide Kinase-Phosphatase (PNKP) is a bifunctional enzyme that possesses both DNA 3'-phosphatase and DNA 5'-kinase activities, which are required for processing termini of single- and double-strand breaks generated by reactive oxygen species (ROS), ionizing radiation and topoisomerase I poisons. Even though PNKP is central to DNA repair, there have been no reports linking PNKP mutations in a Microcephaly, Seizures, and Developmental Delay (MSCZ) patient to cancer. Here, we characterized the biochemical significance of 2 germ-line point mutations in the PNKP gene of a 3-year old male with MSCZ who presented with a high-grade brain tumor (glioblastoma multiforme) within the cerebellum. Functional and biochemical studies demonstrated these PNKP mutations significantly diminished DNA kinase/phosphatase activities, altered its cellular distribution, caused defective repair of DNA single/double stranded breaks, and were associated with a higher propensity for oncogenic transformation. Our findings indicate that specific PNKP mutations may contribute to tumor initiation within susceptible cells in the CNS by limiting DNA damage repair and increasing rates of spontaneous mutations resulting in pediatric glioma associated driver mutations such as ATRX and TP53.

Mutations of the DNA repair gene PNKP in a patient with microcephaly, seizures, and developmental delay (MCSZ) presenting with a high-grade brain tumor.

Brain metastases are a challenging manifestation of renal cell carcinoma. We have a limited understanding of brain metastasis tumor and immune biology, drivers of resistance to systemic treatment, and their overall poor prognosis. Current data support a multimodal treatment strategy with radiation treatment and/or surgery. Nonetheless, the optimal approach for the management of brain metastases from renal cell carcinoma remains unclear. To improve patient care, the authors sought to standardize practical management strategies. They performed an unstructured literature review and elaborated on the current management strategies through an international group of experts from different disciplines assembled via the network of the International Kidney Cancer Coalition. Experts from different disciplines were administered a survey to answer questions related to current challenges and unmet patient needs. On the basis of the integrated approach of literature review and survey study results, the authors built algorithms for the management of single and multiple brain metastases in patients with renal cell carcinoma. The literature review, consensus statements, and algorithms presented in this report can serve as a framework guiding treatment decisions for patients. CA Cancer J Clin. 2022;72:454-489.

An interdisciplinary consensus on the management of brain metastases in patients with renal cell carcinoma.

Electrocorticography (ECoG) language mapping is often performed extraoperatively, frequently involves offline processing, and relationships with direct cortical stimulation (DCS) remain variable. We sought to determine the feasibility and preliminary utility of an intraoperative language mapping approach guided by real-time visualization of electrocorticograms.

Article	Year
Window of Opportunity Clinical Trials to Evaluate Novel Therapies for Brain Tumors. Neurosurgery clinics of North America\| PubMed ID: 33223031	2021
RNAi technology targeting the fusion breakpoint: an opportunity for precision medicine. Neuro-oncology advances\| PubMed ID: 33241214	2020
Delta-24 adenoviral therapy for glioblastoma: evolution from the bench to bedside and future considerations. Neurosurgical focus\| PubMed ID: 33524949	2021
Perfusion-guided endovascular super-selective intra-arterial infusion for treatment of malignant brain tumors. Journal of neurointerventional surgery\| PubMed ID: 34824133	2022
Mutations of the DNA repair gene PNKP in a patient with microcephaly, seizures, and developmental delay (MCSZ) presenting with a high-grade brain tumor. Scientific reports\| PubMed ID: 35354845	2022
An interdisciplinary consensus on the management of brain metastases in patients with renal cell carcinoma. CA: a cancer journal for clinicians\| PubMed ID: 35708940	2022
Intraoperative language mapping guided by real-time visualization of gamma band modulation electrocorticograms: Case report and proof of concept. Neuro-oncology practice\| PubMed ID: 38222047	2024

Chibawanye Ene

Biography

JoVE Journal Publications

Other Publications