Browsing by Author "Gerber, David E."

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    NQO1-dependent, tumor-selective radiosensitization of non-small cell lung cancers
    (American Association for Cancer Research, 2019-04-15) Motea, Edward A.; Huang, Xiumei; Singh, Naveen; Kilgore, Jessica; Williams, Noelle; Xie, Xian-Jin; Gerber, David E.; Beg, Muhammad Shaalan; Bey, Erik A.; Boothman, David A.; Biochemistry and Molecular Biology, School of Medicine
    Purpose: Development of tumor-specific therapies for the treatment of recalcitrant non-small cell lung cancers (NSCLCs) are urgently needed. Here, we investigated the ability of ß-lapachone (ß-lap, ARQ761 in clinical form) to selectively potentiate the effects of ionizing radiation (IR, 1–3 Gy) in NSCLCs that over-express NAD(P)H:Quinone Oxidoreductase 1 (NQO1). Experimental Design: The mechanism of lethality of low dose IR in combination with sublethal doses of ß-lap were evaluated in NSCLC lines in vitro and validated in subcutaneous and orthotopic xenograph models in vivo. Pharmacokinetics and pharmacodynamics (PK/PD) studies comparing single versus co-treatments were performed to validate therapeutic efficacy and mechanism of action. Results: ß-Lap administration after IR treatment hyperactivated PARP, greatly lowered NAD+/ATP levels, and increased DSB lesions over time in vitro. Radiosensitization of orthotopic, as well as subcutaneous, NSCLCs occurred with high apparent cures (>70%), even though 1/8 ß-lap doses reach subcutaneous versus orthotopic tumors. No methemoglobinemia or long-term toxicities were noted in any normal tissues, including mouse liver that expresses the highest level of NQO1 (~12 Units) of any normal tissue. PK/PD responses confirm that IR + ß-lap treatments hyperactivate PARP activity, greatly lower NAD+/ATP levels and dramatically inhibit DSB repair in exposed NQO1+ cancer tissue, while low NQO1 levels and high levels of Catalase in associated normal tissue were protective. Conclusion: Our data suggest that combination of sublethal doses of ß-lap and IR is a viable approach to selectively treat NQO1-overexpressing NSCLC and warrant a clinical trial using low-dose IR + ß-lapachone against patients with NQO1+ NSCLCs.
  • Thumbnail Image
    Item
    Oncologic emergencies and urgencies: A comprehensive review
    (Wiley, 2022-11) Gould Rothberg, Bonnie E.; Quest, Tammie E.; Yeung, Sai-Ching J.; Pelosof, Lorraine C.; Gerber, David E.; Seltzer, Justin A.; Bischof, Jason J.; Thomas, Charles R., Jr.; Akhte, Nausheen; Mamtani, Mira; Stutman, Robin E.; Baugh, Christopher W.; Anantharaman, Venkataraman; Pettit, Nicholas R.; Klotz, Adam D.; Gibbs, Michael A.; Kyriacou, Demetrios N.; Emergency Medicine, School of Medicine
    Patients with advanced cancer generate 4 million visits annually to emergency departments (EDs) and other dedicated, high-acuity oncology urgent care centers. Because of both the increasing complexity of systemic treatments overall and the higher rates of active therapy in the geriatric population, many patients experiencing acute decompensations are frail and acutely ill. This article comprehensively reviews the spectrum of oncologic emergencies and urgencies typically encountered in acute care settings. Presentation, underlying etiology, and up-to-date clinical pathways are discussed. Criteria for either a safe discharge to home or a transition of care to the inpatient oncology hospitalist team are emphasized. This review extends beyond familiar conditions such as febrile neutropenia, hypercalcemia, tumor lysis syndrome, malignant spinal cord compression, mechanical bowel obstruction, and breakthrough pain crises to include a broader spectrum of topics encompassing the syndrome of inappropriate antidiuretic hormone secretion, venous thromboembolism and malignant effusions, as well as chemotherapy-induced mucositis, cardiomyopathy, nausea, vomiting, and diarrhea. Emergent and urgent complications associated with targeted therapeutics, including small molecules, naked and drug-conjugated monoclonal antibodies, as well as immune checkpoint inhibitors and chimeric antigen receptor T-cells, are summarized. Finally, strategies for facilitating same-day direct admission to hospice from the ED are discussed. This article not only can serve as a point-of-care reference for the ED physician but also can assist outpatient oncologists as well as inpatient hospitalists in coordinating care around the ED visit.