Katie Hohenberger, MD

All Publications

• C-Terminal Hsp90 Inhibitors Overcome MEK and BRAF Inhibitor Resistance in Melanoma. Journal of cellular and molecular medicine Subramanian, C., Hohenberger, K. K., Zuo, A., Cousineau, E., Blagg, B., Cohen, M. 2025; 29 (6): e70489

  Abstract

  Targeted therapies for melanoma MEK and BRAF inhibitors fail due to the development of chemoresistance. As Hsp90 inhibitors target client proteins of resistant pathways, we hypothesised that C-terminal Hsp90 inhibitors will target BRAF/MEK inhibitor resistant melanoma cells by overcoming the resistant pathways. Two melanoma cell lines, A375 and A375 MEK/BRAF inhibitor resistant (A375MEKi) were utilised. The inhibitory concentrations (IC50) of two C-terminal Hsp90 inhibitors, KU757 and KU758, were determined by CellTiter Glo. RNA sequencing was performed after treatment with KU757. Pathways targeted by differentially expressed genes were evaluated by David, IPA, GSEA, and by evaluating the cell cycle, apoptosis and oxidative phosphorylation. Expression levels of hub genes were evaluated using Xena and validated by RT-PCR. The survival analysis was performed using UALCAN. A375MEKi was not resistant to the C-terminal Hsp90 inhibitor with a KU757 IC50 of 0.59muM versus 0.64muM and a KU758 IC50 of 0.89muM versus 0.93muM in A375 versus A375MEKi, respectively. RNA sequencing analysis revealed KU757 upregulates cell cycle checkpoint regulation and apoptosis and downregulates genes involved in the peroxisome, AKT/PI3K/MTOR, EIF2, fatty acid metabolism and oxidative phosphorylation. These pathways were further validated through survival analysis that demonstrated potential survival benefit in patients with dysregulated NDUFA7, CDC20, CDC25C, CDK1, VDAC2, HEATR5a, COL4A4, FLT3LG, BMP2, PRKCH and ADMST9. Melanomas often develop concurrent resistance to BRAF and MEK inhibitors. C-terminal Hsp90 inhibition with KU757 appears to overcome these chemo-resistance pathways invitro, downregulating metabolic pathways including oxidative phosphorylation and the cell cycle, warranting further invivo translation. The novel C-terminal HSP90 inhibitor KU757 effectively targets primary and BRAF and MEK inhibitor-resistant melanoma cells equally by affecting oxidative phosphorylation and the cell cycle.

  View details for DOI 10.1111/jcmm.70489

  View details for PubMedID 40135438

• Combination Treatment of Withalongolide a Triacetate with Cisplatin Induces Apoptosis by Targeting Translational Initiation, Migration, and Epithelial to Mesenchymal Transition in Head and Neck Squamous Cell Carcinoma. Nutrients Subramanian, C., Spielbauer, K. K., Pearce, R., Kovatch, K. J., Prince, M. E., Timmermann, B. N., Cohen, M. S. 2022; 14 (24)

  Abstract

  Treatment regimens for head and neck squamous cell carcinoma (HNSCC) typically include cisplatin and radiotherapy and are limited by toxicities. We have identified naturally derived withalongolide A triacetate (WGA-TA) from Physalis longifolia as a lead compound for targeting HNSCC. We hypothesized that combining WGA-TA with cisplatin may allow for lower, less toxic cisplatin doses. HNSCC cell lines were treated with WGA-TA and cisplatin. After treatment with the drugs, the cell viability was determined by MTS assay. The combination index was calculated using CompuSyn. The expression of proteins involved in the targeting of translational initiation complex, epithelial to mesenchymal transition (EMT), and apoptosis were measured by western blot. Invasion and migration were measured using the Boyden-chamber assay. Treatment of MDA-1986 and UMSCC-22B cell lines with either WGA-TA or cisplatin alone for 72 h resulted in a dose dependent decrease in cell viability. Cisplatin in combination with WGA-TA resulted in significant synergistic cell death starting from 1.25 μM cisplatin. Combination treatment with WGA-TA resulted in lower cisplatin dosing while maintaining the downregulation of translational initiation complex proteins, the induction of apoptosis, and the blockade of migration, invasion, and EMT transition. These results suggest that combining a low concentration of cisplatin with WGA-TA may provide a safer, more effective therapeutic option for HNSCC that warrants translational validation.

  View details for DOI 10.3390/nu14245398

  View details for PubMedID 36558560

  View details for PubMedCentralID PMC9782118

• Virtual Resident Mentorship Groups for Fourth Year Medical Students Applying into Otolaryngology-Head and Neck Surgery. The Annals of otology, rhinology, and laryngology Farlow, J. L., Devare, J., Ellsperman, S. E., Haring, C. T., Heft Neal, M. E., Pleasant, T., Spielbauer, K. K., Sylvester, M. J., Xie, Y., Marchiano, E. J. 2022; 131 (2): 198-204

  Abstract

  To create a longitudinal near-peer mentorship program for medical students applying to otolaryngology.A program for longitudinal near-peer mentorship was designed based on a needs analysis of senior medical students. Program objectives were to (1) provide didactic education on common otolaryngology consults, (2) facilitate resident-student networking, and (3) enable applicants to meet other students. Senior otolaryngology residents were matched with medical students from across the United States applying to otolaryngology for a series of online small group meetings. Sessions included resident-designed didactics covering high-yield clinical scenarios and a mentorship component focused on transition to residency topics. Program evaluation included anonymized pre- and post-tests for each didactic session and an anonymous post-program participant survey.There were 40 student participants from across the United States, with an average attendance of 73% of sessions per participant. Performance on didactic testing improved for 2 of the 3 sessions. Participants stated they would be very likely to recommend each session to another student in the future (4.96/5.00, obs = 155). Participants stated the most valuable part of the program was interacting with residents (82% of responses), transition to residency advice (28%), and learning about otolaryngology consults (28%). Suggestions for improvement included expanding content, increasing the number of sessions, and involving additional faculty and residents.A longitudinal virtual experience can be valuable for near-peer mentorship for medical students applying to otolaryngology.

  View details for DOI 10.1177/00034894211015740

  View details for PubMedID 33978510

• Use of rotational thromboelastometry (ROTEM®) to predict thrombotic complications of microvascular head and neck reconstruction. Oral oncology Spielbauer, K. K., Sunde, J., Buchakjian, M., Casper, K. A., Malloy, K. M., Stucken, C. L., Prince, M. E., Rosko, A. J., Schechtman, S., Chinn, S. B., Kumar, S. S., Spector, M. E. 2022; 124: 105515

  View details for DOI 10.1016/j.oraloncology.2021.105515

  View details for PubMedID 34481704

• Time to Surgery and Survival in Head and Neck Cancer. Annals of surgical oncology Heft Neal, M. E., Spielbauer, K. K., Spector, M. E. 2021; 28 (2): 602-603

  View details for DOI 10.1245/s10434-020-09336-2

  View details for PubMedID 33165724

  View details for PubMedCentralID PMC7651805

• Lovastatin protects against cisplatin-induced hearing loss in mice. Hearing research Fernandez, K., Spielbauer, K. K., Rusheen, A., Wang, L., Baker, T. G., Eyles, S., Cunningham, L. L. 2020; 389: 107905

  Abstract

  Cisplatin is used to treat a variety of solid tumors in both children and adults. However, cisplatin has serious side-effects, some of which may permanently affect patients' quality of life following treatment, such as ototoxicity. There is currently no FDA-approved therapy for the prevention or treatment of cisplatin-induced hearing loss. Herein we examine the potential for statins to prevent cisplatin-induced ototoxicity. Statins, a class of drugs commonly used to prevent or manage hypercholesterolemia, have been of clinical utility for decades with dependable outcomes and reliable safety profiles in humans. Statins are known to be protective in animal models of noise-induced and age-related hearing loss. Moreover, studies have demonstrated an additive benefit of statins in cancer treatment. In the current study, lovastatin reduces cisplatin-induced hearing loss in adult mice. Lovastatin-mediated protection was significantly greater among female than male mice, and the dose of lovastatin required for protection was different between the sexes. Taken together our data indicate that lovastatin reduces cisplatin-induced hearing loss in mice and suggest that concurrent statin and cisplatin therapy may represent a feasible clinical strategy for reducing cisplatin-induced ototoxicity that should be explored for future clinical use.

  View details for DOI 10.1016/j.heares.2020.107905

  View details for PubMedID 32062294

  View details for PubMedCentralID PMC7080598

• α-synuclein expression from a single copy transgene increases sensitivity to stress and accelerates neuronal loss in genetic models of Parkinson's disease. Experimental neurology Cooper, J. F., Spielbauer, K. K., Senchuk, M. M., Nadarajan, S., Colaiácovo, M. P., Van Raamsdonk, J. M. 2018; 310: 58-69

  Abstract

  Parkinson's disease (PD) is the second most common neurodegenerative disease and is characterized by the formation of α-synuclein-containing protein aggregates called Lewy bodies within the brain. A crucial role for α-synuclein in the pathogenesis of PD is also suggested by the fact that point mutations, increased copy number, or polymorphisms in the α-synuclein gene SNCA all cause or contribute to the development of PD. In addition to SNCA, an increasing number of other genes have been implicated in PD. While mutations in at least some of these genes have been shown to cause the formation of Lewy bodies, the role of α-synuclein in these genetic forms of PD remains poorly defined. Since C. elegans do not have a homolog of α-synuclein, this organism provides the opportunity to identify synergism between α-synuclein and other genes implicated in PD. To do this, we generated a novel C. elegans model in which wild-type α-synuclein is ubiquitously expressed from a single copy transgene, and examined the resulting effect on phenotypic deficits in PD deletion mutants affecting PARK2/pdr-1, PINK1/pink-1, DJ-1/djr-1.1 and ATP13A2/catp-6. While the PD deletion mutants exhibit only mild phenotypic deficits in absence of α-synuclein, expression of wild-type α-synuclein caused increased sensitivity to multiple stresses, induced deficits in dopamine-dependent behavior, and accelerated loss of dopamine neurons. Overall, these results suggest that the recessive loss of function mutations act together with α-synuclein to cause PD, and that α-synuclein lowering strategies may be effective in genetic forms of PD.

  View details for DOI 10.1016/j.expneurol.2018.09.001

  View details for PubMedID 30194957

  View details for PubMedCentralID PMC6203651

• PD-1 Inhibition Minimally Affects Cisplatin-Induced Toxicities in a Murine Model. Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery Spielbauer, K., Cunningham, L., Schmitt, N. 2018; 159 (2): 343-346

  Abstract

  Immune checkpoint inhibition used in combination with standard cisplatin-based chemotherapy regimens is currently under evaluation in clinical trials for head and neck squamous cell carcinoma (HNSCC). The impact of anti-PD-1 therapy on cisplatin-induced ototoxicity and nephrotoxicity has not been established. Here we use a murine model of cisplatin-induced hearing loss to investigate the impact of anti-PD-1 immunotherapy on auditory brainstem responses (ABRs), distortion product otoacoustic emissions (DPOAEs), serum creatinine, and hair cell and renal histology. We demonstrate only mild worsening of DPOAEs at 14.4 and 16 kHz as well as a mild increase in serum creatinine. Renal and hair cell histology as well as ABR measures were unchanged by PD-1 inhibition. Thus, our data suggest that the use of PD-1 inhibition in conjunction with cisplatin results in toxicities that are similar to those of cisplatin alone.

  View details for DOI 10.1177/0194599818767621

  View details for PubMedID 29609517

  View details for PubMedCentralID PMC6134261

• Cisplatin Alters Antitumor Immunity and Synergizes with PD-1/PD-L1 Inhibition in Head and Neck Squamous Cell Carcinoma. Cancer immunology research Tran, L., Allen, C. T., Xiao, R., Moore, E., Davis, R., Park, S. J., Spielbauer, K., Van Waes, C., Schmitt, N. C. 2017; 5 (12): 1141-1151

  Abstract

  Head and neck squamous cell carcinoma (HNSCC) has been treated for decades with cisplatin chemotherapy, and anti-PD-1 immunotherapy has recently been approved for the treatment of this disease. However, preclinical studies of how antitumor immunity in HNSCC is affected by cisplatin alone or in combination with immunotherapies are lacking. Here, we show that sublethal doses of cisplatin may enhance antigen presentation and T-cell killing in vitro, though cisplatin also upregulates tumor cell expression of PD-L1 and may impair T-cell function at higher doses. In a syngeneic mouse model of HNSCC, concurrent use of cisplatin and anti-PD-L1/PD-1 delayed tumor growth and enhanced survival without significantly reducing the number or function of tumor-infiltrating immune cells or increasing cisplatin-induced toxicities. These results suggest that moderate doses of cisplatin may enhance antitumor immunity by mechanisms other than direct tumor cell killing, which may be further enhanced by anti-PD-L1/PD-1 therapy. Cancer Immunol Res; 5(12); 1141-51. ©2017 AACR.

  View details for DOI 10.1158/2326-6066.CIR-17-0235

  View details for PubMedID 29097421

  View details for PubMedCentralID PMC5712281

• Activation of the mitochondrial unfolded protein response promotes longevity and dopamine neuron survival in Parkinson's disease models. Scientific reports Cooper, J. F., Machiela, E., Dues, D. J., Spielbauer, K. K., Senchuk, M. M., Van Raamsdonk, J. M. 2017; 7 (1): 16441

  Abstract

  While the pathogenesis of Parkinson's disease (PD) is incompletely understood, mitochondrial dysfunction is thought to play a crucial role in disease pathogenesis. Here, we examined the relationship between mitochondrial function and dopamine neuron dysfunction and death using C. elegans mutants for three mitochondria-related genes implicated in monogenic PD (pdr-1/PRKN, pink-1/PINK1 and djr-1.1/DJ-1). We found that pdr-1 and pink-1 mutants exhibit deficits in dopamine-dependent behaviors, but no loss of dopamine neurons, while djr-1.1 mutants showed an increased sensitivity to oxidative stress. In examining mitochondrial morphology and function, we found that djr-1.1 mutants exhibit increased mitochondrial fragmentation leading to decreased rate of oxidative phosphorylation and ATP levels. pdr-1 and pink-1 mutants show an accumulation of dysfunctional mitochondria with age, which leads to activation of the mitochondrial unfolded protein response (mitoUPR). Preventing the upregulation of the mitoUPR with a deletion in atfs-1 results in decreased lifespan and dopamine neuronal loss in pdr-1 and pink-1 mutants but not in wild-type worms. Overall, our results suggest that mutations in pdr-1 and pink-1 cause the accumulation of dysfunctional mitochondria, which activates the mitoUPR to mitigate the detrimental effect of these mutations on dopamine neuron survival.

  View details for DOI 10.1038/s41598-017-16637-2

  View details for PubMedID 29180793

  View details for PubMedCentralID PMC5703891

• Cisplatin is retained in the cochlea indefinitely following chemotherapy. Nature communications Breglio, A. M., Rusheen, A. E., Shide, E. D., Fernandez, K. A., Spielbauer, K. K., McLachlin, K. M., Hall, M. D., Amable, L., Cunningham, L. L. 2017; 8 (1): 1654

  Abstract

  Cisplatin chemotherapy causes permanent hearing loss in 40-80% of treated patients. It is unclear whether the cochlea has unique sensitivity to cisplatin or is exposed to higher levels of the drug. Here we use inductively coupled plasma mass spectrometry (ICP-MS) to examine cisplatin pharmacokinetics in the cochleae of mice and humans. In most organs cisplatin is detected within one hour after injection, and is eliminated over the following days to weeks. In contrast, the cochlea retains cisplatin for months to years after treatment in both mice and humans. Using laser ablation coupled to ICP-MS, we map cisplatin distribution within the human cochlea. Cisplatin accumulation is consistently high in the stria vascularis, the region of the cochlea that maintains the ionic composition of endolymph. Our results demonstrate long-term retention of cisplatin in the human cochlea, and they point to the stria vascularis as an important therapeutic target for preventing cisplatin ototoxicity.

  View details for DOI 10.1038/s41467-017-01837-1

  View details for PubMedID 29162831

  View details for PubMedCentralID PMC5698400

• Delaying aging is neuroprotective in Parkinson's disease: a genetic analysis in C. elegans models. NPJ Parkinson's disease Cooper, J. F., Dues, D. J., Spielbauer, K. K., Machiela, E., Senchuk, M. M., Van Raamsdonk, J. M. 2015; 1: 15022

  Abstract

  Aging is the greatest risk factor for the development of Parkinson's disease (PD). However, the role of aging in the pathogenesis of PD is not known and it is currently uncertain why the symptoms take many decades to develop when inherited mutations that cause the disease can be present from birth. We hypothesize that there are specific changes that take place during the aging process that make cells susceptible to disease-causing mutations that are well-tolerated at younger ages. If so, then interventions that increase lifespan should be beneficial in the treatment of PD. To test this hypothesis, we used the powerful genetics of C. elegans, as this worm has been used extensively in aging research. We crossed transgenic worm models of PD expressing either human mutant α-synuclein (A53T) or LRRK2 (G2019S) with the long-lived insulin-IGF1 receptor mutant, daf-2. The daf-2 mutation increased the lifespan of both PD mutants. The increase in lifespan resulting from the daf-2 mutation rescued the degeneration of dopamine neurons in both worm models of PD and importantly rescued deficits in dopamine-dependent behaviors including basal slowing, ethanol avoidance, and area-restricted searching. Increasing lifespan through daf-2 mutation also delayed the formation of small aggregates in a worm model of PD expressing α-synuclein in the body wall muscle and rescued deficits in resistance to different stresses that were present in the PD mutant worms. Overall, this work suggests that slowing down the aging process may provide an effective treatment for PD.

  View details for DOI 10.1038/npjparkd.2015.22

  View details for PubMedID 28725688

  View details for PubMedCentralID PMC5516561

• Mitochondrial and cytoplasmic ROS have opposing effects on lifespan. PLoS genetics Schaar, C. E., Dues, D. J., Spielbauer, K. K., Machiela, E., Cooper, J. F., Senchuk, M., Hekimi, S., Van Raamsdonk, J. M. 2015; 11 (2): e1004972

  Abstract

  Reactive oxygen species (ROS) are highly reactive, oxygen-containing molecules that can cause molecular damage within the cell. While the accumulation of ROS-mediated damage is widely believed to be one of the main causes of aging, ROS also act in signaling pathways. Recent work has demonstrated that increasing levels of superoxide, one form of ROS, through treatment with paraquat, results in increased lifespan. Interestingly, treatment with paraquat robustly increases the already long lifespan of the clk-1 mitochondrial mutant, but not other long-lived mitochondrial mutants such as isp-1 or nuo-6. To genetically dissect the subcellular compartment in which elevated ROS act to increase lifespan, we deleted individual superoxide dismutase (sod) genes in clk-1 mutants, which are sensitized to ROS. We find that only deletion of the primary mitochondrial sod gene, sod-2 results in increased lifespan in clk-1 worms. In contrast, deletion of either of the two cytoplasmic sod genes, sod-1 or sod-5, significantly decreases the lifespan of clk-1 worms. Further, we show that increasing mitochondrial superoxide levels through deletion of sod-2 or treatment with paraquat can still increase lifespan in clk-1;sod-1 double mutants, which live shorter than clk-1 worms. The fact that mitochondrial superoxide can increase lifespan in worms with a detrimental level of cytoplasmic superoxide demonstrates that ROS have a compartment specific effect on lifespan - elevated ROS in the mitochondria acts to increase lifespan, while elevated ROS in the cytoplasm decreases lifespan. This work also suggests that both ROS-dependent and ROS-independent mechanisms contribute to the longevity of clk-1 worms.

  View details for DOI 10.1371/journal.pgen.1004972

  View details for PubMedID 25671321

  View details for PubMedCentralID PMC4335496