Browsing by Author "Koenig, Jenna"

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    Combinatorial Inhibition of Epigenetic Regulators to Treat Glioblastoma
    (2022-07-29) Burket, Noah; Koenig, Jenna; Saratsis, Amanda
    Glioblastoma (GBM) is a deadly primary brain cancer that affects 12,000 patients in the US annually with a median survival time of 15 months. Temozolomide is the standard-of-care chemotherapy for GBM; however, many tumors are resistant, necessitating the expansion of therapeutic options. EZH2 and JMJD3 are two proteins responsible for epigenetic regulation of the genome via histone methylation, with EZH2 also affecting non-histone targets. Prior studies showed that inhibition of these proteins decreased cell counts and induced radiosensitivity in GBM cells. Thus, we investigated combined use of EZH2 inhibitor, EPZ6438, and JMJD3 inhibitor, GSK-J4, in the treatment of temozolomide-resistant GBM10 cells. Non-irradiated cells were treated with both drugs singly and combined, and counted at 24-, 48-, and 72-hour intervals. Irradiated cells were pre-treated with each drug and combination therapy for three days, irradiated, and then counted at 24-, 48-, and 72-hour intervals. Western blot was used to investigate dsDNA damage biomarker y-H2AX, gene-silencing modification H3K27me3, tumor suppressor p53, EZH2, and JMJD3 expression in non-irradiated and irradiated cells following drug treatment. Single EPZ-6438 and GSK-J4 treatments reduced cell counts with increasing concentration and time. GSK-J4 appears to reduce cell counts more than EPZ-6438 alone, and combinatorial use reduces this further. Western blot reveals increased H3K27me3 expression with GSK-J4 treatment following radiation, but not with EPZ-6438. y-H2AX expression is increased after EPZ-6438 treatment but is not further increased with radiation. Meanwhile, GSK-J4 increased y-H2AX, but only after irradiation. Reduced cell counts following treatment with GSK-J4 may be due to its effects on gene silencing from inhibition of H3K27 demethylation. Additionally, increased dsDNA breaks seen in EPZ-6438 and GSK-J4 supports their roles in radiosensitizing GBM cells. This study highlights the importance of further investigation into GSK-J4 and EPZ-6438 combination therapy in temozolomide-resistant GBM tumors.
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    Combined CDK4/6 and ERK1/2 inhibition enhances anti-tumor activity in NF1-associated plexiform neurofibroma
    (American Association for Cancer Research, 2023) Flint, Alyssa C.; Mitchell, Dana K.; Angus, Steven P.; Smith, Abbi E.; Bessler, Waylan; Jiang, Li; Mang, Henry; Li, Xiaohong; Lu, Qingbo; Rodriguez, Brooke; Sandusky, George E.; Masters, Andi R.; Zhang, Chi; Dang, Pengtao; Koenig, Jenna; Johnson, Gary L.; Shen, Weihua; Liu, Jiangang; Aggarwal, Amit; Donoho, Gregory P.; Willard, Melinda D.; Bhagwat, Shripad V.; Clapp, D. Wade; Rhodes, Steven D.; Pediatrics, School of Medicine
    Purpose: Plexiform neurofibromas (PNF) are peripheral nerve sheath tumors that cause significant morbidity in persons with neurofibromatosis type 1 (NF1), yet treatment options remain limited. To identify novel therapeutic targets for PNF, we applied an integrated multi-omic approach to quantitatively profile kinome enrichment in a mouse model that has predicted therapeutic responses in clinical trials for NF1-associated PNF with high fidelity. Experimental design: Utilizing RNA sequencing combined with chemical proteomic profiling of the functionally enriched kinome using multiplexed inhibitor beads coupled with mass spectrometry, we identified molecular signatures predictive of response to CDK4/6 and RAS/MAPK pathway inhibition in PNF. Informed by these results, we evaluated the efficacy of the CDK4/6 inhibitor, abemaciclib, and the ERK1/2 inhibitor, LY3214996, alone and in combination in reducing PNF tumor burden in Nf1flox/flox;PostnCre mice. Results: Converging signatures of CDK4/6 and RAS/MAPK pathway activation were identified within the transcriptome and kinome that were conserved in both murine and human PNF. We observed robust additivity of the CDK4/6 inhibitor, abemaciclib, in combination with the ERK1/2 inhibitor, LY3214996, in murine and human NF1(Nf1) mutant Schwann cells. Consistent with these findings, the combination of abemaciclib (CDK4/6i) and LY3214996 (ERK1/2i) synergized to suppress molecular signatures of MAPK activation and exhibited enhanced antitumor activity in Nf1flox/flox;PostnCre mice in vivo. Conclusions: These findings provide rationale for the clinical translation of CDK4/6 inhibitors alone and in combination with therapies targeting the RAS/MAPK pathway for the treatment of PNF and other peripheral nerve sheath tumors in persons with NF1.
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    EXTH-43. Targeting the DNA Damage Response Through Combination MDM2 and AKT Inhibitor Therapy Improves Temozolomide Effectiveness in Chemo-Resistant Glioblastoma
    (Oxford University Press, 2023-11-10) Koenig, Jenna; Bailey, Barbara; Alfonso, Anthony; Saadatzadeh, M. Reza; Bijangi-Vishehsaraei, Khadijeh; Pandya, Pankita; Damayanti, Nur; Dobrota, Erika; Young, Courtney; Shannon, Harlan; Pollok, Karen; Graduate Medical Education, School of Medicine
    Temozolomide remains the lone pharmacotherapeutic option for glioblastoma (GBM), yet the development of resistance to temozolomide has been a major challenge contributing to the persistent median < 2-year survival for patients after diagnosis. Tumor heterogeneity and induction of treatment response networks, such as the DNA damage response (DDR), are major contributors to temozolomide resistance in GBM. Targeting DDR treatment response networks, such as the MDM2/p53/p73 and PI3K/AKT/mTOR networks, with small-molecule inhibitors (SMIs) presents an opportunity to disrupt resistance mechanisms and enhance temozolomide efficacy. We utilized a triple drug combination of clinically relevant concentrations of the blood-brain-barrier penetrant SMIs of AKT (ipatasertib; GDC-0068) and MDM2 (idasanutlin; RG7388) with temozolomide to evaluate this targeted strategy using the recurrent, temozolomide-resistant, p53wt GBM10 xenoline. Proliferation studies demonstrated dose-related additive to synergistic inhibition of proliferation at clinically relevant concentrations of ipatasertib and idasanutlin. Further, IncuCyte live-cell imaging demonstrated dose-and time-related growth inhibition of these GBM cells and apoptosis marked by increased cleaved caspase 3 expression following the temozolomide+idasanutlin+ipatasertib triple combination treatment. Cells treated with temozolomide+idasanutlin+ipatasertib also displayed senescence phenotypes, with increased cell cycle arrest and elevated expression of SPiDER β-Gal expression and cell-cycle inhibitors such as p53 and p21. Experiments are in progress to determine the extent to which the effects of temozolomide+idasanutlin+ipatasertib combination therapy are dependent on p53 using siRNA knockdown of p53. In the present study, targeting the temzolomide-induced DNA damage response with idasanutlin+ipatasertib increased the effectiveness of temozolomide. These results indicate that this triple combination may be a promising approach to improving patient outcomes in temozolomide-resistant GBM.
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    NCOG-25. Single-Institution Series of Spinal Ependymoma in Children With NF2-Related Schwannomatosis
    (Oxford University Press, 2023-11-10) Burket, Noah; Koenig, Jenna; Tailor, Jignesh; Neurological Surgery, School of Medicine
    NF2-related schwannomatosis (NrS) is a tumor predisposition syndrome that results in the development of multiple central nervous system tumors, including spinal ependymomas (SP-EPN). SP-EPN are intramedullary tumors that are slow growing but can displace critical nerve pathways in the spinal cord, resulting in motor and sensory deficits that contribute to patient morbidity. Although surgery is the mainstay of treatment, it can also result in high morbidity, resection of sporadic SP-EPN is often curative; however, SP-EPN in NrS patients will often regrow, possibly resulting in additional surgeries and a lifetime of deficits, especially impacting pediatric patients. Yet, natural history and clinical outcomes for pediatric NrS patients with SP-EPN have not been well described. We reviewed 27 pediatric NrS patient cases from 1993 to 2023 at our institution and identified 10 patients with a diagnosis of SP-EPN, with a range of 1-3 tumors present at patient diagnosis. Demographic, clinical, pathologic, and radiologic data were collected from electronic medical records. Median age of diagnosis of NrS was 12 years old (range: 5-17) and median time from NrS diagnosis to SP-EPN diagnosis was 31 days (range: -1-1636). 14 out of 16 (87.5%) initial tumors were in the cervical spine region, with C2 being the most frequently involved level. Two patients underwent resection of their tumors, with both experiencing progression of their disease and one developing paraplegia. The most common symptoms from SP-EPN were pain (30%), motor deficits (30%), and sensory deficits (30%). 40% of the patients had progressive disease at last follow up, with median time from diagnosis to progression of 3.33 years. Median time from SP-EPN to last follow-up was 4.08 years. This series showcases the burden of SP-EPN in pediatric NrS patients, emphasizing the need for further exploration into clinical outcomes and novel treatments for this debilitating condition.
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    Pituitary Adenoma and Social Determinants of Health: Tracing PAths to Better Outcomes
    (2024-09-28) Virtanen , Piiamaria S.; Obeng-Gyasi, Barnabas; Brown, Ethan D. L.; Colter, Austyn; Koenig, Jenna; Burket, Noah; Szilagyi, Halie; Williams, Greer; Halalmeh, Dia; Wang, Hannah S.; Tinkham, Shawn A.; Vetter, Cecelia J.; Richardson, Angela M.