Sally Ditzler
University of Washington
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Featured researches published by Sally Ditzler.
Cancer Research | 2008
Beryl A. Hatton; Elisabeth H. Villavicencio; Karen D. Tsuchiya; Joel I. Pritchard; Sally Ditzler; Barbara Pullar; Stacey Hansen; Sue E. Knoblaugh; Donghoon Lee; Charles G. Eberhart; Andrew Hallahan; James M. Olson
Toward the goal of generating a mouse medulloblastoma model with increased tumor incidence, we developed a homozygous version of our ND2:SmoA1 model. Medulloblastomas form in 94% of homozygous Smo/Smo mice by 2 months of age. Tumor formation is, thus, predictable by age, before the symptomatic appearance of larger lesions. This high incidence and early onset of tumors is ideal for preclinical studies because mice can be enrolled before symptom onset and with a greater latency period before late-stage disease. Smo/Smo tumors also display leptomeningeal dissemination of neoplastic cells to the brain and spine, which occurs in many human cases. Despite an extended proliferation of granule neuron precursors (GNP) in the postnatal external granular layer (EGL), the internal granular layer formed normally in Smo/Smo mice and tumor formation occurred only in localized foci on the superficial surface of the molecular layer. Thus, tumor formation is not simply the result of over proliferation of GNPs within the EGL. Moreover, Smo/Smo medulloblastomas were transplantable and serially passaged in vivo, demonstrating the aggressiveness of tumor cells and their transformation beyond a hyperplastic state. The Smo/Smo model is the first mouse medulloblastoma model to show leptomeningeal spread. The adherence to human pathology, high incidence, and early onset of tumors thus make Smo/Smo mice an efficient model for preclinical studies.
PLOS ONE | 2010
Michelle Jeung Eun Lee; Omid Veiseh; Narayan Bhattarai; Conroy Sun; Stacey Hansen; Sally Ditzler; Sue E. Knoblaugh; Donghoon Lee; Richard G. Ellenbogen; Miqin Zhang; James M. Olson
Background Recent advances in nanotechnology have led to the development of biocompatible nanoparticles for in vivo molecular imaging and targeted therapy. Many nanoparticles have undesirable tissue distribution or unacceptably low serum half-lives. Pharmacokinetic (PK) and biodistribution studies can help inform decisions determining particle size, coatings, or other features early in nanoparticle development. Unfortunately, these studies are rarely done in a timely fashion because many nanotechnology labs lack the resources and expertise to synthesize radioactive nanoparticles and evaluate them in mice. Methodology/Principal Findings To address this problem, we developed an economical, radioactivity-free method for assessing serum half-life and tissue distribution of nanoparticles in mice. Iron oxide nanoparticles coated with chitosan and polyethylene glycol that utilize chlorotoxin as a targeting molecule have a serum half-life of 7–8 hours and the particles remain stable for extended periods of time in physiologic fluids and in vivo. Nanoparticles preferentially distribute to spleen and liver, presumably due to reticuloendothelial uptake. Other organs have very low levels of nanoparticles, which is ideal for imaging most cancers in the future. No acute toxicity was attributed to the nanoparticles. Conclusions/Significance We report here a simple near-infrared fluorescence based methodology to assess PK properties of nanoparticles in order to integrate pharmacokinetic data into early nanoparticle design and synthesis. The nanoparticles tested demonstrate properties that are excellent for future clinical imaging strategies and potentially suitable for targeted therapy.
Science Translational Medicine | 2015
Richard A. Klinghoffer; S. Bahram Bahrami; Beryl A. Hatton; Jason Frazier; Alicia Moreno-Gonzalez; Andrew D. Strand; William S. Kerwin; Joseph Casalini; Derek J. Thirstrup; Sheng You; Shelli M. Morris; Korashon L. Watts; Mandana Veiseh; Marc Grenley; Ilona Tretyak; Joyoti Dey; Michael Carleton; Emily Beirne; Kyle Pedro; Sally Ditzler; Emily J. Girard; Thomas L. Deckwerth; Jessica A. Bertout; Karri A. Meleo; Ellen H. Filvaroff; Rajesh Chopra; Oliver W. Press; James M. Olson
Simultaneous in vivo assessment of multiple cancer drugs and drug combinations using microinjection technology predicts systemic response in model tumors and has shown feasibility for assessment of drug efficacy in a pilot study in cancer patients. There’s no place like the human Animal models of human tumors and dish cultures of cancer cells are not sufficient to predict an individual patient’s response to therapy. In the emerging era of personalized medicine, why limit ourselves to rodent models and engineered in vitro tumor models when we can study a drug directly in the patient’s tumor? This question was answered by Klinghoffer et al. by creating a microinjection system called CIVO that delivers small doses of up to eight different drugs simultaneously, directly into the tumor. The tumors could then be removed and evaluated for various markers of cancer response; in short, the authors looked for markers of cell death and drug-related mechanisms of action. By using an injection-tracking dye, Klinghoffer and colleagues could see where the drug was deposited and then use an automated analyzer for quantitative image processing along the 6-mm injection tract. In mouse models of human lymphoma, the authors were able to correctly predict systemic responsiveness to doxorubicin or vincristine—or not, in the case of resistant lymphomas. They also uncovered unexpected drug sensitivities, which were not picked up by traditional cell culture, including to novel anticancer agents, and confirmed these in vivo. The authors pilot-tested the device in dog and human patients, demonstrating the ability of CIVO to inject and track local tumor response to chemotherapies. Ultimately, such a personalized approach to drug sensitivity testing will allow for rational selection of therapeutics while sparing patients the pain—and time—associated with ineffective treatments. A fundamental problem in cancer drug development is that antitumor efficacy in preclinical cancer models does not translate faithfully to patient outcomes. Much of early cancer drug discovery is performed under in vitro conditions in cell-based models that poorly represent actual malignancies. To address this inconsistency, we have developed a technology platform called CIVO, which enables simultaneous assessment of up to eight drugs or drug combinations within a single solid tumor in vivo. The platform is currently designed for use in animal models of cancer and patients with superficial tumors but can be modified for investigation of deeper-seated malignancies. In xenograft lymphoma models, CIVO microinjection of well-characterized anticancer agents (vincristine, doxorubicin, mafosfamide, and prednisolone) induced spatially defined cellular changes around sites of drug exposure, specific to the known mechanisms of action of each drug. The observed localized responses predicted responses to systemically delivered drugs in animals. In pair-matched lymphoma models, CIVO correctly demonstrated tumor resistance to doxorubicin and vincristine and an unexpected enhanced sensitivity to mafosfamide in multidrug-resistant lymphomas compared with chemotherapy-naïve lymphomas. A CIVO-enabled in vivo screen of 97 approved oncology agents revealed a novel mTOR (mammalian target of rapamycin) pathway inhibitor that exhibits significantly increased tumor-killing activity in the drug-resistant setting compared with chemotherapy-naïve tumors. Finally, feasibility studies to assess the use of CIVO in human and canine patients demonstrated that microinjection of drugs is toxicity-sparing while inducing robust, easily tracked, drug-specific responses in autochthonous tumors, setting the stage for further application of this technology in clinical trials.
Molecular and Cellular Biology | 2012
Joyoti Dey; Sally Ditzler; Sue E. Knoblaugh; Beryl A. Hatton; Janell M. Schelter; Michele A. Cleary; Brig Mecham; Lucy B. Rorke-Adams; James M. Olson
ABSTRACT Deregulated developmental processes in the cerebellum cause medulloblastoma, the most common pediatric brain malignancy. About 25 to 30% of cases are caused by mutations increasing the activity of the Sonic hedgehog (Shh) pathway, a critical mitogen in cerebellar development. The proto-oncogene Smoothened (Smo) is a key transducer of the Shh pathway. Activating mutations in Smo that lead to constitutive activity of the Shh pathway have been identified in human medulloblastoma. To understand the developmental and oncogenic effects of two closely positioned point mutations in Smo, we characterized NeuroD2-SmoA2 mice and compared them to NeuroD2-SmoA1 mice. While both SmoA1 and SmoA2 transgenes cause medulloblastoma with similar frequencies and timing, SmoA2 mice have severe aberrations in cerebellar development, whereas SmoA1 mice are largely normal during development. Intriguingly, neurologic function, as measured by specific tests, is normal in the SmoA2 mice despite extensive cerebellar dysplasia. We demonstrate how two nearly contiguous point mutations in the same domain of the encoded Smo protein can produce striking phenotypic differences in cerebellar development and organization in mice.
Cancer Research | 2017
Jason Frazier; Jessica A. Bertout; William S. Kerwin; Alicia Moreno-Gonzalez; Joey R. Casalini; Marc Grenley; Emily Beirne; Kori L. Watts; Andy Keener; Derek J. Thirstrup; Ilona Tretyak; Sally Ditzler; Chelsea D. Tripp; Kevin Choy; Sarah Gillings; Megan N. Breit; Karri A. Meleo; Vanessa Rizzo; Chamisa L. Herrera; James A. Perry; Ravi K. Amaravadi; James M. Olson; Richard A. Klinghoffer
The vision of a precision medicine-guided approach to novel cancer drug development is challenged by high intratumor heterogeneity and interpatient diversity. This complexity is rarely modeled accurately during preclinical drug development, hampering predictions of clinical drug efficacy. To address this issue, we developed Comparative In Vivo Oncology (CIVO) arrayed microinjection technology to test tumor responsiveness to simultaneous microdoses of multiple drugs directly in a patients tumor. Here, in a study of 18 canine patients with soft tissue sarcoma (STS), CIVO captured complex, patient-specific tumor responses encompassing both cancer cells and multiple immune infiltrates following localized exposure to different chemotherapy agents. CIVO also classified patient-specific tumor resistance to the most effective agent, doxorubicin, and further enabled assessment of a preclinical autophagy inhibitor, PS-1001, to reverse doxorubicin resistance. In a CIVO-identified subset of doxorubicin-resistant tumors, PS-1001 resulted in enhanced antitumor activity, increased infiltration of macrophages, and skewed this infiltrate toward M1 polarization. The ability to evaluate and cross-compare multiple drugs and drug combinations simultaneously in living tumors and across a diverse immunocompetent patient population may provide a foundation from which to make informed drug development decisions. This method also represents a viable functional approach to complement current precision oncology strategies. Cancer Res; 77(11); 2869-80. ©2017 AACR.
PLOS ONE | 2016
Joyoti Dey; William S. Kerwin; Marc Grenley; Joseph Casalini; Ilona Tretyak; Sally Ditzler; Derek Thirstrup; Jason Frazier; Daniel W. Pierce; Michael Carleton; Richard A. Klinghoffer
While advances in high-throughput screening have resulted in increased ability to identify synergistic anti-cancer drug combinations, validation of drug synergy in the in vivo setting and prioritization of combinations for clinical development remain low-throughput and resource intensive. Furthermore, there is currently no viable method for prospectively assessing drug synergy directly in human patients in order to potentially tailor therapies. To address these issues we have employed the previously described CIVO platform and developed a quantitative approach for investigating multiple combination hypotheses simultaneously in single living tumors. This platform provides a rapid, quantitative and cost effective approach to compare and prioritize drug combinations based on evidence of synergistic tumor cell killing in the live tumor context. Using a gemcitabine resistant model of pancreatic cancer, we efficiently investigated nine rationally selected Abraxane-based combinations employing only 19 xenografted mice. Among the drugs tested, the BCL2/BCLxL inhibitor ABT-263 was identified as the one agent that synergized with Abraxane® to enhance acute induction of localized apoptosis in this model of human pancreatic cancer. Importantly, results obtained with CIVO accurately predicted the outcome of systemic dosing studies in the same model where superior tumor regression induced by the Abraxane/ABT-263 combination was observed compared to that induced by either single agent. This supports expanded use of CIVO as an in vivo platform for expedited in vivo drug combination validation and sets the stage for performing toxicity-sparing drug combination studies directly in cancer patients with solid malignancies.
Scientific Reports | 2017
Joyoti Dey; Thomas L. Deckwerth; William S. Kerwin; Joseph Casalini; Angela Merrell; Marc Grenley; Connor Burns; Sally Ditzler; Chantel P. Dixon; Emily Beirne; Kate C. Gillespie; Edward Kleinman; Richard A. Klinghoffer
Aberrant regulation of BCL-2 family members enables evasion of apoptosis and tumor resistance to chemotherapy. BCL-2 and functionally redundant counterpart, MCL-1, are frequently over-expressed in high-risk diffuse large B-cell lymphoma (DLBCL). While clinical inhibition of BCL-2 has been achieved with the BH3 mimetic venetoclax, anti-tumor efficacy is limited by compensatory induction of MCL-1. Voruciclib, an orally bioavailable clinical stage CDK-selective inhibitor, potently blocks CDK9, the transcriptional regulator of MCL-1. Here, we demonstrate that voruciclib represses MCL-1 protein expression in preclinical models of DLBCL. When combined with venetoclax in vivo, voruciclib leads to model-dependent tumor cell apoptosis and tumor growth inhibition. Strongest responses were observed in two models representing high-risk activated B-cell (ABC) DLBCL, while no response was observed in a third ABC model, and intermediate responses were observed in two models of germinal center B-cell like (GCB) DLBCL. Given the range of responses, we show that CIVO, a multiplexed tumor micro-dosing technology, represents a viable functional precision medicine approach for differentiating responders from non-responders to BCL-2/MCL-1 targeted therapy. These findings suggest that the combination of voruciclib and venetoclax holds promise as a novel, exclusively oral combination therapy for a subset of high-risk DLBCL patients.
Cancer Research | 2016
Joyoti Dey; Joseph Casalini; Sally Ditzler; Matt Biery; Angela Merrell; Derek Thirstrup; Marc Grenley; Richard A. Klinghoffer
Triple negative breast cancer (TNBC) is a highly heterogeneous disease, notoriously challenging to treat with standard chemotherapy options, and therefore is an area of intense focus for discovery of novel effective combination therapies. Here we used a previously described technology platform called CIVO, which enables assessment of multiple drugs and drug combinations simultaneously in living tumors, to identify drug combinations that result in synergistic anti-tumor activity in the HCC1187 model of TNBC. Our study focused on agents that combine with Voruciclib, a novel clinical stage oral CDK inhibitor with potent activity ( Citation Format: Joyoti Dey, Joseph Casalini, Sally Ditzler, Matt Biery, Angela Merrell, Derek Thirstrup, Marc Grenley, Richard Klinghoffer. Voruciclib, a clinical stage oral CDK inhibitor, sensitizes triple negative breast cancer xenografts to proteasome inhibition. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2835.
Clinical Cancer Research | 2015
Richard A. Klinghoffer; Alicia Moreno-Gonzalez; Michael Carleton; Marc Grenley; Beryl A. Hatton; Jason Frazier; William S. Kerwin; Ilona Tretyak; Nathan Hedin; Joyoti Dey; Joseph Casalini; Sally Ditzler; James R. Olson; Nathan Caffo
Assessment of anti-cancer drug efficacy is an imprecise and challenging undertaking. Early candidate selection is typically based on results from systemically treated animal models and later by performance in human trials where patients are exposed to often toxic levels of drug, prior to obtaining readouts of tumor response. In both of these testing models, only one drug can be tested at a time. Using these methods, over 90% of candidate new oncology drugs fail to provide benefit for patients in human clinical trials. To improve the predictive value of preclinical candidate selection in animal models and enable a new type of pre-Phase 1 toxicity-sparing comparative drug efficacy study in humans, amenable for use in the solid tumor clinic, we have developed a technology platform called CIVO™. This platform allows for simultaneous assessment of multiple drugs or drug combinations directly in a single solid tumor to assess efficacy, resistance and drug synergies. In this study, precise, controlled delivery of classic chemotherapy drugs vincristine and doxorubicin induced spatially defined (ranging 0.3 – 2.0 mm in diameter), readily detectable, and mechanism-specific cellular changes around sites of tumor microinjection across three xenograft models of lymphoma. The extent of apoptosis induced via CIVO™ microdosing of each drug ( The data presented here generated in drug-responsive and non-responsive solid tumors in the preclinical setting sets the stage for future application of this technology to demonstrate tumor responsiveness to novel drug candidates in the context of human patients. Citation Format: Richard Klinghoffer, Alicia Moreno-Gonzalez, Michael Carleton, Marc Grenley, Beryl Hatton, Jason Frazier, William Kerwin, Ilona Tretyak, Nathan Hedin, Joyoti Dey, Joseph Casalini, Sally Ditzler, James Olson, Nathan Caffo. A platform to assess multiple therapy options simultaneously in a patient9s own tumor. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr A39.
Cancer Research | 2015
Alicia Moreno Gonzalez; Jason Frazier; William S. Kerwin; Jessica A. Bertout; Joseph Casalini; Sally Ditzler; Nathan Caffo; Richard A. Klinghoffer
We report the initial clinical findings of a device platform to test multiple therapeutic options simultaneously in individual living tumors within a clinical patient population, detailing for the first time comparative effects of different drugs within individual intact tumors. Most early cancer drug discovery is performed under in vitro conditions in cell-based models that poorly represent the disease they are intended to represent and have a poor track record for predicting success in subsequent clinical trials. To enable in vivo analysis of anti-cancer agent efficacy at earlier stages of drug development, and to potentially enable toxicity-sparing assessment of novel agents in the oncology clinic, we have developed a technology platform called CIVO™. CIVO allows for simultaneous assessment of up to eight drugs or drug combinations in a single solid tumor while the tumor is still in the patient. Controlled microinjection-based delivery of doxorubicin, docetaxel, mafosfamide, and gemcitabine was tested in twelve patients in the canine sarcoma clinic. Drugs were co-injected in a columnar array with UV fluorescent beads resulting in easy-to-identify bands of drug at 95% of the injection sites, each at a distinct position of the patient9s tumor. Tumors were resected 72h following microinjection and were subjected to multiplexed analyses for tumor response which included drug-induced ablation of sarcoma cells, apoptosis, DNA damage, mitotic arrest, immune infiltration, and feedback activation of oncogenic pathways. The CIVO-introduced drug microdoses induced spatially-defined graded, and mechanism-specific cellular changes around sites of drug exposure in a drug and patient-specific manner. Consistent with the use of doxorubicin as first line therapy in the soft tissue sarcoma clinic, the frequency and extent of response of localized tumor kill induced by Doxorubicin (6/9 patients) exceeded those of all other agents tested, with Docetaxel being next most effective (2/6 patients), and Gemcitabine being the least effective (0/9 patients). Interestingly, almost all confirmed sites of response showed evidence of mTOR pathway upregulation, suggesting that mTOR pathway activation represents a potential common mechanism of chemo-resistance across sarcoma patients exists to multiple chemo-toxic agents. We are currently exploring combinations of 1st line sarcoma drugs with mTOR inhibitors in the canine sarcoma clinic with CIVO. This data represents the first time differential effects of multiple drugs have been captured within individual intact tumors in a clinical population. Along with early responses observed in the human clinic, this sets the stage for application of this technology to identify which novel agents are likely to succeed or fail in subsequent clinical trials. Citation Format: Alicia Moreno Gonzalez, Jason Frazier, William Kerwin, Jessica Bertout, Joseph Casalini, Sally Ditzler, Nathan Caffo, Richard A. Klinghoffer. A platform to test multiple therapies simultaneously in the intact tumors of cancer patients: Initial clinical experience. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2020. doi:10.1158/1538-7445.AM2015-2020