Justine Yang Bruce

A phase II study of 2-methoxyestradiol nanocrystal colloidal dispersion alone and in combination with sunitinib malate in patients with metastatic renal cell carcinoma progressing on sunitinib malate

SummaryBackground Current treatment for metastatic renal cell cancer with vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKI) have provided improved overall survival, but complete responses are rare. We conducted a multicenter phase II study to evaluate the objective response rate of 2-methoxyestradiol (2ME2 NCD) alone and in combination with sunitinib for patients with metastatic renal cell carcinoma who have progressed on sunitinib alone. Methods Adults with metastatic kidney cancer were stratified depending on whether they were still taking sunitinib or had discontinued sunitinib therapy at the time of registration. Patients were treated with 2ME2 NCD alone or in combination with sunitinib. The primary endpoint was objective response rate. Results In total, 17 patients were enrolled, and 12 were evaluable for response (arm A, n = 7; arm b, n = 5). In arm A, four patients had the best response of stable disease, and three patients developed disease progression. In arm B, three patients had a best response of stable disease, and two patients had disease progression. One patient continued to receive treatment for a total of 14 cycles before developing disease progression. Fatigue was the most common observed toxicities. Thirty five percent of patients required discontinuation of therapy secondary to toxicities. Conclusions 2ME2 NCD had minimal anti-tumor activity, with no observed objective responses. The study was terminated because 2ME2 NCD was not found to be tolerable at the recommended phase 2 dose in this patient population. A newer 2ME2 analog is in development with a more favorable toxicity profile and increased potency.

Phase II study of single-agent orteronel (TAK-700) in patients with nonmetastatic castration-resistant prostate cancer and rising prostate-specific antigen

Purpose: Orteronel (TAK-700) is an investigational, nonsteroidal, oral, inhibitor of androgen synthesis with greater specificity for 17,20-lyase than for 17α-hydroxylase. We investigated orteronel without steroids in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC; M0). Experimental Design: Patients with nmCRPC and rising prostate-specific antigen (PSA) received orteronel 300 mg twice daily until PSA progression, metastases, or unacceptable toxicity. The primary endpoint was percentage of patients achieving PSA ≤0.2 ng/mL (undetectable levels) at 3 months. Secondary endpoints included safety, PSA response, time to metastases, and correlated endpoints. Results: Thirty-nine patients with a median baseline PSA doubling time of 2.4 months (range, 0.9–9.2) received a median of fourteen 28-day treatment cycles. PSA decreased >30% in 35 patients and 6 (16%) achieved PSA ≤ 0.2 ng/mL at 3 months. Median times to PSA progression and metastasis were 13.8 and 25.4 months, respectively. Kaplan–Meier estimates of freedom from PSA progression were 57% and 42% at 12 and 24 months, and of freedom from metastasis were 94% and 62% at 12 and 24 months, respectively. At 3 months, median testosterone declined by 89% from baseline. Adverse events led to therapy discontinuation in 12 patients and grade ≥3/4 adverse events occurred in 22 patients. Most frequent all-cause adverse events included fatigue (64%), hypertension (44%), diarrhea (38%), and nausea (33%), which were primarily grade 1/2. Conclusions: Single-agent orteronel produced marked and durable declines in PSA in patients with nmCRPC. Orteronel has moderate but manageable toxicities and its chronic administration without steroids appears feasible. Clin Cancer Res; 20(16); 4218–27. ©2014 AACR.

A Randomized Phase II Trial of Short-Course Androgen Deprivation Therapy With or Without Bevacizumab for Patients With Recurrent Prostate Cancer After Definitive Local Therapy

PURPOSE Patients with recurrent prostate cancer after local treatment make up a heterogeneous population for whom androgen deprivation therapy (ADT) is the usual treatment. The purpose of this randomized phase II trial was to investigate the efficacy and toxicity of short-course ADT with or without bevacizumab in men with hormone-sensitive prostate cancer. PATIENTS AND METHODS Eligible patients had an increasing prostate-specific antigen (PSA) of ≤ 50 ng/mL and PSA doubling time of less than 18 months. Patients had either no metastases or low burden, asymptomatic metastases (lymph nodes < 3 cm and five or fewer bone metastases). Patients were randomly assigned 2:1 to a luteinizing hormone-releasing hormone agonist, bicalutamide and bevacizumab or ADT alone, for 6 months. The primary end point was PSA relapse-free survival (RFS). Relapse was defined as a PSA of more than 0.2 ng/mL for prostatectomy patients or PSA of more than 2.0 ng/mL for primary radiation therapy patients. RESULTS Sixty-six patients received ADT + bevacizumab and 36 received ADT alone. Patients receiving ADT + bevacizumab had a statistically significant improvement in RFS compared with patients treated with ADT alone (13.3 months for ADT + bevacizumab v 10.2 months for ADT alone; hazard ratio, 0.47; 95% CI, 0.29 to 0.77; log-rank P = .002). Hypertension was the most common adverse event in patients receiving ADT + bevacizumab (36%). CONCLUSION ADT combined with bevacizumab resulted in an improved RFS for patients with hormone-sensitive prostate cancer. Long-term follow-up is needed to determine whether some patients have a durable PSA response and are able to remain off ADT for prolonged periods. Our data provide rationale for combining vascular endothelial growth factor-targeting therapy with ADT in hormone-sensitive prostate cancer.

Phase 1b Study of Abiraterone Acetate Plus Prednisone and Docetaxel in Patients with Metastatic Castration-resistant Prostate Cancer

Coadministration of docetaxel and abiraterone acetate plus prednisone (AA + P) may benefit patients with metastatic castration-resistant prostate cancer (mCRPC) because of complementary mechanisms of action. COU-AA-206 was a phase 1b study to determine the safe dose combination of docetaxel and AA + P in three cohorts of chemotherapy-naïve mCRPC patients. Twenty-two patients received escalating doses of docetaxel plus AA + P. The primary endpoint was the proportion of patients with a dose-limiting toxicity (DLT) between weeks 2 and 7. The recommended phase 2 dose (RP2D) was the highest safe combination of docetaxel plus AA + P. Prostate-specific antigen (PSA) changes and intensive pharmacokinetic parameters for each drug were evaluated. Docetaxel 75mg/m2 + AA 1000mg + P 10mg was deemed the RP2D, with DLT in one of six patients. PSA declines from baseline of ≥50% and ≥90% were observed for 85.7% and 66.7% of patients, respectively. During median follow-up of 14.5 mo, eight patients had PSA progression and six had radiographic progression or died. Systemic exposure was comparable for docetaxel and abiraterone when given alone or in combination. Studies are ongoing to confirm the efficacy of potent androgen receptor-targeted therapy plus taxane in early mCRPC. PATIENT SUMMARY The combination of hormonal therapy and chemotherapy may improve outcomes in men with metastatic prostate cancer. This study demonstrates the ability to combine the hormonal therapy agent abiraterone acetate, plus prednisone, and the chemotherapy drug docetaxel with an acceptable side effect profile. A high rate of prostate-specific antigen decline was seen, but the study was small and additional research is needed before this becomes a standard approach.

Cotargeting mTORC and EGFR Signaling as a Therapeutic Strategy in HNSCC.

Head and neck squamous cell carcinomas (HNSCC) are frequently altered along the PI3K/AKT/mTORC signaling axis. Despite excellent preclinical data, the use of compounds targeting this pathway as monotherapy has been underwhelming in initial clinical trials, and identification of predictive biomarkers remains challenging. To investigate mTORC-specific inhibition, we tested catalytic mTORC (AZD8055) and PI3K/mTORC (NVP-BEZ-235) inhibitors ± cetuximab in a panel of HNSCC cell lines and patient-derived xenografts (PDX). Cell lines were assayed for response to all agents and siRNA knockdown of targets by multiple approaches. All cell lines showed similar response to both drug and siRNA inhibition of both PI3K and mTORC pathways, with anti-EGFR combination producing modest additive effect. Five PDX models that presented PIK3CA mutation or intrinsic cetuximab resistance were treated with a combination of cetuximab and AZD8055. In vivo single-agent mTORC inhibition inhibited growth of one PIK3CA-mutant cancer, but had little effect on any PIK3CAWT or a second PIK3CA-mutant model. In all models, the combination therapy showed greater growth delay than monotherapy. The uniform ability of PI3K and mTORC inhibition to suppress the growth of HNSCC cells highlights the pathways role in driving proliferation. Although single-agent therapy was largely ineffective in vivo, improved response of combination treatment in an array of PDXs suggests the potential for adding a catalytic mTORC inhibitor to cetuximab therapy. Overall, these results add to a growing body of evidence, suggesting that approaches that attempt to match biomarkers to the optimal therapy in HNSCC remain complex and challenging. Mol Cancer Ther; 16(7); 1257–68. ©2017 AACR.

Testing Personalized Medicine Using Patient-Derived Xenografts of Head and Neck Cancer

HPV status, or treatmentwithRTalone, concurrent chemotherapy, or upfront laryngectomy. We defined radiation-resistance as persistent or recurrent diseasewithin 3 years of receiving treatment. Early-stage LSCCwas defined as stage I or II tumors without lymph node involvement. Candidate genes associated with the radiation resistance included NFE2L2, KEAP1, CUL3, HRAS, NRAS, NOTCH2, NOTCH3, KRAS, RAF1, BCL-2, and BIRC5. Results: Twenty LSCC tumors were categorized as either radiation sensitive (RS, NZ9) or radiation resistant (RR, NZ11). Six were early-stage tumors (RR: NZ3 and RS: NZ3). Basic demographic factors were balanced between the 2 groups. Among all 20 samples, we found increased somatic mutations in the NOTCH pathway in RR patients (NOTCH 2: 44% vs. 0%, PZ .04; NOTCH 3 44% vs. 11%, PZ.19). In the 6 early-stage LSCC patients, we found all 3 RR tumors to have mutations in the KEAP1/ NFE2L2 pathway, while none of the RS tumors had mutations (PZ.014). Conclusion: In RR patients, there was a higher somatic mutational burden involving the NOTCH family. Interestingly, all early-stage LSCC patients with RR (NZ3) had mutations in the KEAP1/NRF2 oxidative stress pathway. In LSCC patients, downregulation of the KEAP1/NRF2 oxidative stress pathway may result in RT resistance. Further validation in a larger population is warranted. Alterations in both the NOTCH and KEAP1/ NRF2 oxidative stress pathway may serve as genomic determinants to predict radiation resistance in LSCC. Author Disclosure: D. Farquhar: None. S. Sheth: None. A. Mazul: None. P. Little: None. D.N. Hayes: None. J.P. Zevallos: None.

Radiosensitization of adenoid cystic carcinoma with MDM2 inhibition

Purpose: Adenoid cystic carcinoma (ACC) is a rare cancer arising from the major or minor salivary gland tissues of the head and neck. There are currently no approved systemic agents or known radiosensitizers for ACC. Unlike the more common head and neck squamous cell carcinomas that frequently harbor TP53 mutations, ACCs contain TP53 mutations at a rate of <5%, rendering them an attractive target for MDM2 inhibition. Experimental Design: We report the successful establishment and detailed characterization of a TP53-WT ACC patient-derived xenograft (PDX), which retained the histologic features of the original patient tumor. We evaluated this model for response to the MDM2 inhibitor AMG 232 as monotherapy and in combination with radiotherapy. Results: AMG 232 monotherapy induced modest tumor growth inhibition, and radiation monotherapy induced a transient tumor growth delay in a dose-dependent fashion. Strikingly, combination treatment of AMG 232 with radiotherapy (including low-dose radiotherapy of 2 Gy/fraction) induced dramatic tumor response and high local tumor control rates 3 months following treatment. Posttreatment analysis revealed that although both AMG 232 and radiotherapy alone induced TP53 tumor-suppressive activities, combination therapy amplified this response with potent induction of apoptosis after combination treatment. Conclusions: These data identify that MDM2 inhibition can provide potent radiosensitization in TP53-WT ACC. In light of the absence of effective systemic agents for ACC, the powerful response profile observed here suggests that clinical trial evaluation of this drug/radiotherapy combination may be warranted to improve local control in this challenging malignancy. Clin Cancer Res; 23(20); 6044–53. ©2017 AACR.

Abstract 51: Potential and challenges in co-targeting mTORC and EGFR signaling as a therapeutic strategy in HNSCC

Background: Head and neck squamous cell carcinomas (HNSCCs) have high rates of mutation and other alterations along the PI3K/AKT/mTORC signaling axis. This has led to interest in the use of therapeutics targeting this pathway; however, identifying reliable predictive biomarkers to guide patient selection remains challenging. Despite excellent preclinical data, the use of these compounds as monotherapy has been underwhelming in initial clinical trials. The EGFR monoclonal antibody cetuximab remains the only approved targeted agent for HNSCC and with reasonable toxicity profiles, has potential use in combination therapy. Methods: Both catalytic mTORC (AZD8055) and PI3K/mTORC(NVP-BEZ-235) inhibitors were tested +/- cetuximab in several in vitro and in vivo pre-clinical models. A panel of HNSCC cell lines and patient derived xenografts (PDX) were evaluated for PI3K/AKT/mTORC pathway mutation by sequencing and potential protein biomarker by immunoblot and IHC. Cell lines were assayed for sensitivity to all three agents by growth inhibition and clonogenic survival assay. DNA replication (BrdU uptake) and apoptosis (Capase 3/7 activity) were investigated to assess the mechanism of inhibition. The specificity of the molecular targeted effects was confirmed by siRNA knockdown. Five unique PDX models that presented PIK3CA mutation or intrinsic cetuximab resistance were treated with a combination of cetuximab and the dual mTORC inhibitor AZD8055 in a nude mouse model. Matched PDX derived cell strains were generated to investigate differences in response observed in in vitro and in vivo settings. Results: Assessment of the panel of HNSCC cell lines by mutational hotspot sequencing did not reveal any obvious sensitizing mutations, whereas putative protein biomarkers (e.g. PIK3CA, pAKT) were elevated in some cell lines. All cell lines showed modest response to both PI3K/mTORC and dual mTORC inhibition. The addition of cetuximab to either agent produced modest additive effect. Mechanistic studies revealed that growth inhibition rather than death induction was the major anticancer effect. SiRNA knockdown showed similar molecular signaling and functional effects to drug inhibition. Using the PDX models, in vivo single agent mTORC inhibition inhibited growth of a PIK3CA mutant cancer, but had no effect on any PIK3CAWT or a second PIK3CA mutant model. In all models the combination therapy showed greater growth delay than monotherapy. In matched PDX derived cell strains, in vitro responses were similar when grown in 3D culture but cells displayed greater sensitivity when grown in 2D culture, suggesting that tumor microenvironment contributes to response. Conclusions: The uniform ability of PI3K/mTORC and mTORC inhibition to suppress the growth of HNSCC cells highlights the role of this signaling pathway to drive the proliferation. In vivo, despite some PDX models meeting likely selection criteria, the single agent therapy was largely ineffective. Conversely, the combination treatment produced growth delay and suggests the potential for adding a catalytic mTORC inhibitor to cetuximab therapy for HNSCC patients. Overall, these results add to a growing body of evidence suggesting approaches that attempt to match genetic alternation or other biomarker to the optimal therapy in HNSCC remain complex and challenging. Citation Format: Adam D. Swick, Prashanth J. Prabakaran, Margot C. Miller, Amal M. Javaid, Michael M. Fisher, Emmanuel Sampene, Irene M. Ong, Mari Iida, Deric L. Wheeler, Kwangok P. Nickel, Justine Y. Bruce, Randall J. Kimple. Potential and challenges in co-targeting mTORC and EGFR signaling as a therapeutic strategy in HNSCC [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 51.

Patient-Derived Adenoid Cystic Carcinoma Xenografts to Examine Personalized Radiation Therapy.

Purpose/Objective(s): Clinical radiotherapy has made significant advances since its inception, growing into a tertiary specialty with significant contributions to curative and palliative treatments of cancer and health care costs. A major limitation to its appropriate application, however, has been the lack of measurable biological indicators, or biomarkers that can reliably identify patients with cancers that are more or less likely to respond to these treatments. Materials/Methods: We conducted large-scale profiling of cellular survival after exposure to radiation in a diverse collection of 534 genetically annotated human tumor cell lines. Using data derived from a single, validated experimental platform we studied the genetic determinants of survival after radiation in 534 human cancer cell lines across 26 cancer types. We correlated radiation sensitivity and genomic parameters using the information-based similarity index, which is sensitive to non-linear relationships and offers better resolution at the high end of the matching range. Results: We showed that individual SCNA, gene mutations, and the basal expression of individual genes and gene sets correlate with radiation survival. By studying a large number of cancer types, we found that genetic correlates in any single cancer type can be found in other cancer types as well (e.g., Nrf2 activation in non-small cell lung cancer and hepatobiliary cancer and AR expression in prostate and breast adenocarcinomas). This supports the view that although diverse, cancer genomes reflect combinations of a limited number of functionally relevant events that can confer therapeutic resistance across cancer types. Conclusion: We identified several new genetic determinants of response to DNA damage that can have predictive capacity by identifying the likelihood of response to therapy and, consequently, prognosis. The potential for stratification of patients from heterogeneous populations to genetically similar subgroups can help guide the transition of radiotherapy from a generic population-based approach to one that is more personalized. Author Disclosure: B. Yard: None. D. Adams: None. P. Tamayo: None. P. Hammerman: None. M. Abazeed: None.

Abstract 3044: Patient-derived adenoid cystic carcinoma xenografts to study molecular target modulation of tumor radiosensitivity

Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA Background: Adenoid cystic carcinoma (ACC) is a relatively rare cancer that typically arises in salivary tissues of the head and neck region. Hallmark characteristics include slow growth rate, peri-neural tumor spread, and a high propensity for late distant metastasis. Surgery and radiation are the mainstays of treatment with no effective systemic agents to date. Due to infrequency, studies of novel therapeutics are not routinely feasible. In addition, whether these tumors can be sensitized to radiation by concurrent chemotherapy is not known. We report here the establishment and examination of ACC patient derived xenografts (PDX) to investigate the efficacy of novel chemotherapies and combinations of chemotherapy and radiation. Methods: PDXs have been established and maintained in NOD-SCID gamma (NSG) mice from both research biopsies and surgical specimens. Common cancer-associated mutations in both the primary patient tumor and PDX were identified using the Illumina TruSeq Amplicon Cancer panel. Well described immunohistochemical markers of ACC were used to compare histological characteristics between the primary tumor and PDX. The ACC PDX was engrafted into the flanks of nude mice and treated with focal radiotherapy (5 Gy x 8 fractions delivered twice weekly), a panel of chemotherapeutic agents, or combination radiochemotherapy. Tumor size was measured over time and comparisons between treatment groups made by the extra-sum-of-squares f test. Results: PDXs established from ACC maintain the histologic and physical characteristics of the primary tumor. Targeted mutational analysis of ACC identified expected alterations based on previously reported large scale sequencing of other human tumors including mutations in the receptor tyrosine kinases(RTKs) cKit and KDR/VEGFR2. Based on identified tumor mutations, several targeted therapies were selected including dovitinib, a multi-RTK inhibitor, BEZ235, a PI3K/mTORC inhibitor, and cetuximab, an EGFR mAB. Treatment with each of these compounds showed varying degrees of growth inhibition without evidence of frank tumor regression. However, combining these drugs with radiation demonstrated significantly improved tumor control in comparison to drug alone. Conclusions: Studies using our PDX model suggest that several molecular targeting agents can significantly augment the impact of radiation on ACC tumor growth. These preliminary data identify the rationale to investigate selected molecular drug/radiation combinations for ACC, particularly when driven by tumor specific genetic biomarkers. Expansion of these ACC studies may be valuable to advance the design of new investigational treatment strategies for this challenging tumor. Citation Format: Prashanth Prabakaran, Kwangok P. Nickel, David T. Yang, Lauryn R. Werner, Justine Y. Bruce, Aaron M. Wieland, Timothy M. McCulloch, Gregory K. Hartig, Paul M. Harari, Adam D. Swick, Randall J. Kimple. Patient-derived adenoid cystic carcinoma xenografts to study molecular target modulation of tumor radiosensitivity. [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 3044.