Activity In Anaplastic Thyroid Cancer Research Articles

Inhibition of MEK Signaling Attenuates Cancer Stem Cell Activity in Anaplastic Thyroid Cancer.

Background: Anaplastic thyroid cancer (ATC) is highly aggressive and has very limited treatment options. Recent studies suggest that cancer stem cell (CSC) activity in ATC could underlie this recurrence and resistance to treatment. The recent approval by the U.S. Food and Drug Administration of the combined treatment of BRAF and MEK inhibitors for ATC patients has shown some efficacy in patients harboring the BRAFV600E mutation. However, it was unknown whether the combined treatment could affect the CSC activity. This study explores the effects of the BRAF and MEK inhibitors on CSC activity in human ATC cells. Methods: Using three human ATC cells, THJ-11T, THJ-16T, and 8505C cells, we evaluated the effects of dabrafenib (a BRAF kinase inhibitor), trametinib (an MEK inhibitor), or a combined treatment of the two drugs on the CSC activity by tumorsphere formation, Aldefluor assays, expression profiles of key CSC markers, immunohistochemistry, and in vivo xenograft mouse models. Furthermore, we also used confocal imaging to directly visualize the effects on drugs on CSCs by the SORE6-mCherry reporter in cultured cells and xenograft tumor cells. Results: The BRAF inhibitor, dabrafenib, had weak efficacy, while the MEK inhibitor, trametinib, showed strong efficacy in attenuating the CSC activity, as evidenced by suppression of CSC marker expression, tumorsphere formation, and Aldefluor assays. Using ATC cells expressing a fluorescent CSC SORE6 reporter, we showed reduction of CSC activity in the rank order of combined > trametinib > dabrafenib through in vitro and in vivo xenograft models. Molecular analyses showed that suppression of CSC activity by these drugs was, in part, mediated by attenuation of the transcription by dampening the RNA polymerase II activity. Conclusions: Our analyses demonstrated the presence of CSCs in ATC cells. The inhibition of CSC activity by the MEK signaling could partially account for the efficacy of the combined treatment shown in ATC patients. However, our studies also showed that not all CSC activity was totally abolished, which may account for the recurrence observed in ATC patients. Our findings have provided new insights into the molecular basis of efficacy and limitations of these drugs in ATC patients.

Abstract 5505: Combination nitazoxanide and auranofin treatment has synergistic anticancer activity in anaplastic thyroid cancer and act by enhanced activation of multiple cell death pathways

Abstract Purpose: Anaplastic thyroid cancer (ATC) is one of the most aggressive human cancers, with a median survival time of 6 months and with no current curative treatment. We have used quantitative high-throughput screening (qHTS) of clinically approved or investigational agents to identify candidate compounds for ATC therapy. As monotherapy for most cancers is not effective, we used combination drug matrix screening of highly active compounds from our single agent qHTS to identify compound combinations that may show synergistic effect. In this study, we evaluated the anticancer activity of nitazoxanide and auranofin combination treatment and its mechanism of action and biomarkers of treatment response in in vitro and in vivo models of ATC. Experimental Design: We used four (8505C, C643, SW1736, THJ16T) ATC cell lines in in vitro and in vivo ATC models to evaluate the safety and efficacy of this combination treatment compared to single agent and vehicle control. Results: Combination nitazoxanide and auranofin treatment synergistically inhibited cellular proliferation (p<0.001) and inhibited colony formation and migration (p<0.001) in ATC cell lines. We observed cellular oxidative stress with significant increase in ROS levels in the combination treatment group (p<0.001). Nitazoxanide treatment alone and in combination with auranofin caused G1/G0 arrest in cell cycle, induced autophagy (increased LC3BII expression) and later apoptosis. Auranofin treatment alone and in combination with nitazoxanide induced ferroptosis (decreased GPX4 expression and intracellular GSH/GSSG ratios). RNA-Seq analysis, to identify biomarkers of response, showed >7-fold increase in HMOX-1 (heme oxygenase 1) with combination treatment which was validated by western blot. Combination treatment significantly inhibited tumor growth as compared to single agents (p<0.01) and had no significant treatment-related toxicity in vivo. Analysis of tumor samples showed significantly increased LC3BII expression by immunohistochemistry and reduced GPX4 mRNA expression (p<0.0001) with combination treatment compared to control in vivo. Conclusions: Combination nitazoxanide and auranofin treatment has synergistic anticancer activity in both in vitro and in vivo ATC models. The synergistic activity of the combination is due to enhanced G1/G0 arrest, greater activation of autophagy, apoptosis and ferroptosis than single drug treatment. LC3BII, HMOX-1 and GPX4 levels could be useful biomarkers of treatment response to combination nitazoxanide and auranofin. Citation Format: Chandrayee Ghosh, Viswanath Gunda, Jiangnan Hu, Lisa Zhang, Ya-Qin Zhang, Min Shen, Electron Kebebew. Combination nitazoxanide and auranofin treatment has synergistic anticancer activity in anaplastic thyroid cancer and act by enhanced activation of multiple cell death pathways. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5505.

Blocking CDK7-Mediated NOTCH1-cMYC Signaling Attenuates Cancer Stem Cell Activity in Anaplastic Thyroid Cancer.

Background: Anaplastic thyroid cancer (ATC) is an aggressive solid cancer in humans with few treatment options. Recent studies suggest that aberrant gene transcription could contribute to aggressive ATC progression. To test this hypothesis, we assessed if blocking cyclin-dependent protein 7 (CDK7) activity could impede ATC progression through attenuation of cancer stem cell (CSC) activity. Methods: We treated cell lines isolated from human ATC (THJ-11T and -16T) and xenograft mice induced by these cells with the CDK7 inhibitor THZ1. Through integrative transcriptome analyses we found that the NOTCH1-cMYC signaling axis was a potential target of CDK7 inhibition in ATC. To determine the regulatory action of NOTCH1-cMYC signaling in CSC maintenance, we evaluated the effect of a selective NOTCH1 inhibitor, crenigacestat, on CSC capacities in ATC. Results: THZ1 markedly inhibited proliferation of ATC cells and xenograft tumor growth by blocking cell cycle progression and inducing apoptosis. NOTCH1 was sensitive to suppressive transcription mediated by CDK7 inhibition and was highly enriched in tumorspheres from ATC cells. Treatment of ATC cells with either crenigacestat or THZ1 blocked formation of tumorspheres, decreased aldehyde dehydrogenase activity, and suppressed in vivo initiation and growth of tumors induced by ATC cells, indicating that NOTCH1 was a critical regulator of CSC activity in ATC. Furthermore, we demonstrated that cMYC was a downstream target of NOTCH1 signaling that collaboratively maintained CSC activity in ATC. Of note, genomic analysis showed that low CDK7 expression contributed to longer disease-free survival of thyroid cancer patients. Conclusions: NOTCH1 is a newly identified CSC regulator. Targeting NOTCH1-cMYC signaling is a promising therapeutic strategy for ATC.

Abstract LBA033: YM155 induces DNA damage and cell death in anaplastic thyroid cancer cells by inhibiting DNA topoisomerase IIα at the ATP binding site

Abstract Introduction: Anaplastic thyroid cancer (ATC) is among the most aggressive of all human cancers with a median survival of 4.3 months. Currently, there is no effective treatment for most ATC patients - surgery, radiation, and chemotherapy all fail to significantly prolong ATC patient survival. YM155, first identified as a survivin inhibitor, was highlighted in a high-throughput screen performed by the National Cancer Institute, killing anaplastic thyroid cancer cells in vitro and in vivo. However, there was no association between survivin expression and response to YM155 in clinical trials (not including ATC), and YM155 has been mostly abandoned for development despite favorable pharmacokinetic and toxicity profiles. A number of additional mechanisms have been proposed for YM155. The purpose of this study was to investigate the mechanisms underlying YM155-mediated ATC cell death. Methods: ATC cell line THJ16T was used as the model for this study. AlamarBlue was used to measure cell viability. Immunofluorescent detection of phosphorylated histone H2AX (γ-H2AX, p-Ser139) foci was used as a surrogate marker for double-strand DNA breaks. siRNA was used to knockdown topoisomerase 2α (Top2α), and Lipofectamine-3000 was used to overexpress Top2α plasmids. In-vivo complex of enzyme assay was used to measure the association between Top2α and DNA. Modeling software Molecular Operating Environment and the crystal structure of human Top2α bound to AMP-PNP (Protein Data Bank # 1ZXM) were used to estimate binding affinities for ATP and YM155 in the ATP binding site of Top2α. Site-directed mutagenesis was used to introduce mutation Ser148 → Ala into a recombinant human Top2α. Results: Previously, we presented gene expression data from ATC patients showing significant overexpression of Top2α compared to benign thyroid samples. ATC cell lines that overexpress Top2α are more sensitive to YM155 and exhibit larger increases in DNA damage with YM155 treatment. In this study, ATC cells grown to be resistant to YM155 show decreased expression of Top2α, and overexpression of Top2α re-sensitizes resistant cells to YM155. Molecular modeling shows favorable binding for YM155 in the Top2α ATP binding site and identifies key amino acids for YM155-Top2α interaction. An engineered Top2α mutant abrogates the effect of YM155 as measured by cell viability and DNA damage assays, confirming the contribution of Top2α to YM155 mechanism of action. Conclusions: Our results strongly suggest that Top2α is an important target mediating YM155’s anticancer activity in ATC. We propose that Top2α inhibition by YM155 leads to DNA damage and eventual cell death. Given YM155's potent anti-proliferative effects in ATC cells with sparing of benign thyroid cells, along with a plausible mechanism of action, we suggest further evaluation and optimization of YM155 for future clinical application in ATC. In conclusion, our study lays the foundation for targeting the enzymatic activity of Top2α as a novel therapeutic strategy for the treatment of ATC, with YM155 serving as the predicate drug. Citation Format: Ryan Mackay, Paul Weinberger, Elahe Mahdavian, Qinqin Xu. YM155 induces DNA damage and cell death in anaplastic thyroid cancer cells by inhibiting DNA topoisomerase IIα at the ATP binding site [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA033.

Precision medicine in aggressive thyroid cancer: Moving beyond multitargeted tyrosine kinase inhibitors

Precision medicine in aggressive thyroid cancer: Moving beyond multitargeted tyrosine kinase inhibitors

Leukocytosis and PTHrP-Mediated Hypercalcemia: Ominous Signs in an Indolent Thyroid Nodule

Introduction/Background: Anaplastic thyroid cancer is a rare thyroid malignancy with a bad prognosis. There are few systemic markers, as thyroglobulin is not usually synthesized in these poorly differentiated malignancies. Clinical Case - Diagnostic Evaluation, Treatment, and Follow Up: A 70-year old man presented in 2016 with a right thyroid nodule, slowly growing since 2012. The nodule was 10cm on neck CT and ultrasound showed a hyperechoic mass with central hypoechoic area, and coarse calcifications. Fine needle biopsy showed a follicular neoplasm. By 2019, neck CT showed enlargement of the nodule to 13 cm. Repeat thyroid biopsy was benign. Lobectomy was recommended due to size but not performed. In 2020, he developed neck discomfort and painful thigh swelling. WBC was significantly elevated at 27,000 (4000-10000) /mm3. Ultrasound showed no evidence of necrosis or abscess in the nodule. WBC rose progressively to 96,000/mm3 (ANC 94,200). CT chest showed further enlargement of the thyroid mass, a soft tissue shoulder mass and lung nodules suspicious for metastases. Laryngoscopy revealed a distorted larynx from external compression, and possible vocal-fold involvement (motion impairment) without airway compromise. Biopsy of the shoulder mass, lung nodule, and thigh masses all showed metastatic anaplastic thyroid cancer. Full infectious disease evaluation and molecular testing for BCR-ABL and JAK2 mutations were negative. Thus, leukocytosis was determined to be reactive in the setting of malignancy. Serum calcium of 14.7 mg/dL (8.5 - 10.6mg/dL) prompted hospital admission. Bone metastases were not visible on imaging. Hypercalcemia was treated effectively (to 8.3mg/dL) with IV fluids, calcitonin and IV bisphosphonates. Workup revealed suppression of PTH to 4 pg/mL (15-65 pg/mL) and low 25 Vitamin D of 21 ng/mL (30-80ng/L). Subsequently PTHrP was elevated at 53.4 pmol/L (<2.3pmol/L) and 1,25 Vitamin D inappropriately normal at 48.9 pg/mL (20- 79.3pg/mL), suggested humoral hypercalcemia of malignancy. The patient declined further treatment beyond hospice care. Clinical Lesson/Conclusion: Significant, sudden leukocytosis and hypercalcemia prompted further evaluation of his long-standing apparently benign thyroid nodule leading to a diagnosis of anaplastic thyroid cancer. Presumably this mass had been a follicular thyroid cancer, misdiagnosed on cytology, that subsequently de-differentiated. There are uncommon reports of leukocytosis complicating anaplastic thyroid cancer, where elevated GCSF and IL-6 were noted. We suspect this same etiology here. Hypercalcemia is extremely rare other than one report of PTHrP-secreting anaplastic thyroid cancer. Thus, high, rising calcium and PTHrP levels may reflect level of disease activity in anaplastic thyroid cancer.

Preclinical and clinical combination therapies in the treatment of anaplastic thyroid cancer.

Anaplastic thyroid cancer (ATC) is the most aggressive form ofthyroidcancer, and novel therapies are urgently needed to prolong patient survival and improve clinical outcomes. Very few scientific reviews have examined the literature on combination therapies with the goal of describing the available preclinical and clinical data and suggesting future clinical combination treatment schedules. The present review focuses on preclinical and clinical studies of drug combination therapies in ATC. The relevant literature from PubMed and Scopus was reviewed in this article; the ClinicalTrials.gov database was searched for clinical trials not yet published. Recent data from preclinical models strongly support the idea that combination treatments that utilize drugs from different antineoplastic classes have synergistic antitumour activity in ATC. However, rapid translation of these therapies into the clinic is impeded by the difficulty in recruiting enough patients for randomized clinical trials. Although promising results have been obtained in preclinical studies, additional clinical research is required to elucidate the efficacy of combination treatments for clinical practice.

Everolimus in Anaplastic Thyroid Cancer: A Case Series.

Background: Anaplastic thyroid cancer (ATC) is a very aggressive disease and accounts for over 50% of thyroid-cancer related deaths. mTOR inhibition has shown anti-tumor activity in ATC. We report our experience treating patients with ATC with everolimus off-protocol.Methods: Patients with confirmed ATC and treated with everolimus at DFCI were identified and reviewed retrospectively. NexGen sequencing was performed, and radiologic responses were correlated with mutational profile.Results: Five patients were treated from 2013 to 2016. Three patients had a response, which included one patient who achieved a partial response for 27.9 months, and two patients who had stable disease for 3.7 and 5.9 months, respectively. Genomic analysis was available in two patients and revealed that the partial responder had mutations involving the PI3K/mTOR pathway.Conclusion: Everolimus has anti-tumor activity in ATC, and responses may correlate with mutations involving the PI3K/mTOR pathway. Further studies are warranted.

PI3K/mTOR inhibition potentiates and extends palbociclib activity in anaplastic thyroid cancer.

Anaplastic thyroid carcinoma (ATC) is the most aggressive form of thyroid cancer. Despite its low incidence, it accounts for a disproportionate number of thyroid cancer-related deaths, because of its resistance to current therapeutic approaches. Novel actionable targets are urgently needed to prolong patient survival and increase their quality of life. Loss and mutation of the RB1 tumor suppressor are rare events in ATC, which suggests that therapies directed at inhibiting the cyclin D/CDK4 complexes, responsible for RB phosphorylation and inactivation, might be effective in this tumor type. In fact, we found that the CDK4/6 inhibitor, palbociclib, strongly inhibits proliferation in all the RB1 wild type ATC cell lines tested. Efficacy was also observed in vivo, in a xenograft model. However, ATC cells rapidly developed resistance to palbociclib. Resistance was associated with increased levels of cyclin D1 and D3. To counter cyclin D overexpression, we tested the effect of combining palbociclib with the PI3K/mTOR dual inhibitor, omipalisib. Combined treatment synergistically reduced cell proliferation, even in cell lines that do not carry PI3K-activating mutations. More importantly, low-dose combination was dramatically effective in inhibiting tumor growth in a xenograft model. Thus, combined PI3K/mTOR and CDK4/6 inhibition is a highly promising novel approach for the treatment of aggressive, therapy-resistant thyroid cancer.

Vandetanib has antineoplastic activity in anaplastic thyroid cancer, in vitro and in vivo.

The antitumor activity of vandetanib [a multiple signal transduction inhibitor including the RET tyrosine kinase, epidermal growth factor receptor(EGFR), vascular endothelial growth factor(VEGF) receptor(VEGFR), ERK and with antiangiogenic activity], in primary anaplastic thyroid cancer(ATC) cells, in the human cell line 8305C [undifferentiated thyroid cancer(TC)] and in an ATC‑cell line (AF), was investigated in the present study. Vandetanib (1and100nM; 1, 10, 25and50µM) was tested by WST‑1, apoptosis, migration and invasion assays: in primary ATC cells, in the 8305C continuous cell line, and in AF cells; and in 8305C cells in CD nu/nu mice. Vandetanib significantly reduced ATC cell proliferation (P<0.01, ANOVA), induced apoptosis dose‑dependently (P<0.001, ANOVA), and inhibited migration (P<0.01) and invasion (P<0.001). Furthermore, vandetanib inhibited EGFR, AKT and ERK1/2 phosphorylation and downregulated cyclinD1 in ATC cells. In 8305C and AF cells, vandetanib significantly inhibited the proliferation, inducing also apoptosis. 8305C cells were injected subcutaneously in CD nu/nu mice and tumor masses became detectable after 30days. Vandetanib (25mg/kg/day) significantly inhibited tumor growth and VEGF‑A expression and microvessel density in 8305C tumor tissues. In conclusion, the antitumor and antiangiogenic activity of vandetanib is very auspicious in ATC, opening the way to a future clinical evaluation.

Lenvatinib exhibits antineoplastic activity in anaplastic thyroid cancer in vitro and in vivo

Lenvatinib is an oral, multitargeted tyrosine kinase inhibitor(TKI) of VEGFR1-VEGFR3, FGFR1-FGFR4, PDGFRα, RET and v-kit Hardy-Zuckerman4 feline sarcoma viral oncogene homolog(KIT) signaling networks involved in tumor angiogenesis. We have evaluated the antitumor activity of lenvatinib in primary anaplastic thyroid cancer (ATC) cells, in the human cell line 8305C (undifferentiated thyroid cancer) and in an ATC-cell line (AF). The AF cell line was obtained from the primary ATC cultures and was the one that grew over 50passages. The effect of lenvatinib (1 and 100nM; and 1, 10, 25 and 50µM) was investigated in primary ATC, 8305C and AF cells as well as in AF cells in CDnu/nu mice. Lenvatinib significantly reduced ATC cell proliferation(P<0.01, ANOVA) and increased the percentage of apoptotic ATC cells (P<0.001, ANOVA). Furthermore, lenvatinib inhibited migration (P<0.01) and invasion(P<0.001) in ATC. In addition, lenvatinib inhibited EGFR, AKT and ERK1/2 phosphorylation and downregulated cyclinD1 in the ATC cells. Lenvatinib also significantly inhibited 8305C and AF cell proliferation, increasing apoptosis. AF cells were subcutaneously injected into CDnu/nu mice and tumor masses were observed 20days later. Tumor growth was significantly inhibited by lenvatinib(25mg/kg/day), as well as the expression of VEGF-A and microvessel density in the AF tumor tissues. In conclusion, the antitumor and antiangiogenic activities of lenvatinib may be promising for the treatment of anaplastic thyroid cancer, and may consist a basis for future clinical therapeutic applications.

Salvage Lenvatinib Therapy in Metastatic Anaplastic Thyroid Cancer.

Historical anaplastic thyroid cancer (ATC) outcomes have been terrible, with a median survival of only five months and <20% one-year survival. Improved outcomes are now achieved with aggressive initial therapy in stages IVA and IVB disease, but patients with distant metastatic disease (stage IVC) still do poorly; improved therapies are sorely needed. Kinase inhibitors have emerged as promising agents in the therapy of advanced medullary and differentiated thyroid cancer, but there are limited data regarding the use of lenvatinib in ATC. The aim of this study was to delineate clinical outcomes in a series of patients with advanced ATC in response to lenvatinib therapy. A retrospective analysis was conducted involving all lenvatinib-treated Mayo Clinic ATC patients in 2015. Of 28 distinct ATC patients seen in 2015, three (11%) with metastatic disease of ECOG performance status 2-3 were treated with lenvatinib. Two patients were male; age range at ATC diagnosis was 57-84 years. All three patients attained successful local control of their disease with surgery and/or combined chemoradiotherapy. Lenvatinib was offered as the second, third, or fourth line of therapy at the time of metastatic disease progression. Two patients incurred minor responses to therapy, with structural regression of distant metastatic tumor disease soon after starting lenvatinib treatment (at one to two months), while one patient achieved stable disease, but no Response Evaluation Criteria In Solid Tumors partial responses resulted. Overall survival after starting lenvatinib was two, six, and seven months. Fatigue and hypertension were prominent, and one patient developed pulmonary emboli while on lenvatinib. This initial single-institution experience suggests that lenvatinib may have some disease-modifying activity in metastatic ATC that is otherwise refractory to cytotoxic chemotherapy. Unfortunately, observed benefits were transient, and toxicities were prominent. Clinical trials are required to ascertain better the utility of lenvatinib in the management of advanced ATC.

Abstract 2527: The drug combination sorafenib and quinacrine targets the expression of Mcl-1 - an anti-apoptotic protein and candidate prognostic factor in Anaplastic Thyroid Cancer (ATC)

Abstract Anaplastic thyroid cancer (ATC) is a rare, highly aggressive form of thyroid cancer that frequently is resistant to conventional therapy and therefore requires the development of efficacious novel therapy. Sorafenib, a multi-kinase inhibitor that inhibits the RAF, MEK and ERK kinases, was recently approved by the FDA for late stage metastatic differentiated thyroid cancer but appears to have limited activity in ATC by itself. Sorafenib-based drug combinations with complimentary drug targets are being pursued and evaluated preclinically. However, sorafenib generates a significant number of adverse events in thyroid cancer patients and drug combinations including sorafenib needs to be carefully tailored with respect to toxicity and efficacy. We have previously shown that quinacrine, a potent small molecule inhibitor of NFKB signaling, combine favorably with several cytotoxic drugs to target hepatocellular and colorectal cancer cells. Quinacrine is an inexpensive drug, has a well established safety profile in human subjects and is being evaluated in cancer clinical trials. Subsequently, we decided to evaluate the efficacy of the drug combination of quinacrine and sorafenib in ATC. Our combinatorial dose-response modulation of quinacrine with sorafenib suggests a synergistic drug-drug interaction with respect to growth stasis in a panel of ATC cells in vitro, as defined by Chou-Talalay. Furthermore, in vivo the drug combination of sorafenib and quinacrine significantly improved survival compared to vehicle control and the current first line chemotherapeutic doxorubicin in a mouse thyroid orthotopic xenograft model of ATC. Dose-escalation toxicity studies in mice suggest that the drug combination was well tolerated and did not trigger synergistic toxicities compared to either drug alone. Significantly less gastrointestinal injury, the most commonly observed toxicity in our study, was present following treatment with the drug combination of sorafenib and quinacrine compared to treatment with doxorubicin alone. Western blot analysis suggests that the anti-apoptotic Bcl-2 family member Mcl-1 is a target for the drug combination. Indeed, immunohistochemical (IHC) analysis of resected ATC and non-neoplastic thyroid tissues from patients confirmed overexpression of Mcl-1 in ATC indicating target availability. Interestingly, multi-regression analysis of our patient IHC data suggest that high Mcl-1 expression together with tumor size prognosticated poor survival in ATC patients suggesting that Mcl-1 overexpression was linked to a more aggressive tumor behavior. In conclusion, our findings suggest that quinacrine in combination with sorafenib may be a novel and potentially cost effective therapeutic strategy to target Mcl-1, whose expression potentially may be linked to the disease progression of ATC. Citation Format: Junaid Abdulghani, Jean-Nicholas Gallant, Prashanth Gokare, Timothy Cooper, Tiffany Whitcomb, Jiangang Liao, Jing Liu, David Goldenberg, Niklas K. Finnberg, Wafik S. El-Deiry. The drug combination sorafenib and quinacrine targets the expression of Mcl-1 - an anti-apoptotic protein and candidate prognostic factor in Anaplastic Thyroid Cancer (ATC). [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 2527. doi:10.1158/1538-7445.AM2015-2527

Therapeutic strategies in the management of patients with metastatic anaplastic thyroid cancer

Anaplastic thyroid cancer (ATC) is a rare and deadly malignancy. There is a need to speed up and support clinical research. This review article focuses on the new molecules that have been developed for the treatment of this aggressive tumor. Improvement in the knowledge of pathogenesis and genetics of ATC led to the development of a variety of new molecules that may be used to treat this disease. In summary, these molecules are proteasome inhibitors, Aurora kinase inhibitors, vascular targeting agents, and gene therapies. All these molecules demonstrated a potentially therapeutic activity in metastatic ATC. To date, the largest prospective randomized multicenter, open-label, trial was conducted with combretastatin-A4. More efficient drugs need to be developed through multinational efforts.

Phase II Trial of Sorafenib in Patients with Advanced Anaplastic Carcinoma of the Thyroid

Anaplastic thyroid cancer (ATC) is a rare but highly aggressive malignancy with a median survival of 3-5 months. The BRAF oncogene is mutated to its active form in up to 24% of ATC cases. Sorafenib is a tyrosine kinase inhibitor that acts on the RAF-1 serine/threonine kinase. In preclinical mouse models, sorafenib inhibits the growth of ATC xenografts and improves survival. No study of sorafenib in ATC has been conducted. We conducted a multi-institutional phase II trial of sorafenib in patients with ATC who had failed up to two previous therapies. The primary endpoint of the trial was the Response Evaluation Criteria In Solid Tumors (RECIST)-defined imaging response rate. Twenty patients with ATC were treated with sorafenib 400 mg twice daily. Two of the 20 patients had a partial response (10%) and an additional 5 of 20 (25%) had stable disease. The duration of response in the two responders was 10 and 27 months, respectively. For the patients with stable disease, the median duration was 4 months (range 3-11 months). The overall median progression-free survival was 1.9 months with a median and a 1-year survival of 3.9 months and 20%, respectively. Toxicity was manageable and as previously described for sorafenib, including hypertension and skin rash. Sorafenib has activity in ATC, but at a low frequency and similar to our previous experience with fosbretabulin. One patient with a response had previously progressed on fosbretabulin. Toxicities were both predictable and manageable.

Pazopanib and Paclitaxel Synergize in Anaplastic Thyroid Cancer

Abstract Combined use with pazopanib may improve paclitaxel activity in anaplastic thyroid cancer.

A multi-institutional phase II trial of pazopanib monotherapy in advanced anaplastic thyroid cancer.

5544 Background: Pazopanib, an orally bioavailable multitargeted inhibitor of kinases including VEGF-R, demonstrated impressive activity in metastatic differentiated thyroid cancer (49% durable RECIST PRs) and promising preclinical activity in anaplastic thyroid cancer (ATC) models, prompting its evaluation also as a candidate therapeutic in advanced ATC. Methods: A multicenter single arm phase II trial of 800 mg pazopanib daily was undertaken with the primary endpoint of RECIST response rate. The trial was designed such that there would be a 90% chance of detecting a response rate of &gt;20% at the 0.10 significance level when the true tumor response rate is &gt;5%. A pre-specified stopping rule designated that enrollment would cease unless 1 or more RECIST PRs+CRs were observed in the first 14 of 33 potential patients. Eligibility required informed consent, &gt;18 years of age, performance status ECOG 0-2, systolic blood pressure (BP) &lt;140 mm Hg and diastolic BP &lt;90 mm Hg at entry, QTc interval &lt;480 msecs, and measurable disease by RECIST criteria. Anatomical imaging and toxicity evaluations were required every 4 weeks. Results: Sixteen patients were enrolled. One patient withdrew prior to therapy, leaving 15 evaluable patients – 33.3% were male, with a median age of 66 years (range 45-77); 11 of 15 patients had progressed through prior systemic therapy. Four patients required 1-2 dose reductions, with the most common severe toxicities (CTC-AE version 3.0 grades 3-5) hypertension (13%) and pharyngolaryngeal pain (13%). Reasons for treatment discontinuation included: disease progression (12 pts), death on study due to a vascular event possibly related to treatment (1 pt.), and intolerability (radiation recall tracheitis – 1 pt, and uncontrolled hypertension – 1 pt). Although transient disease regression was observed in several patients, there were no confirmed RECIST tumor responses, triggering study closure at time of interim analysis. Two patients are alive with disease 9.9 months and 2.9 years post-registration; the remaining 13 died of disease. The median time to progression was 62 days and the median survival time was 111 days. Conclusions: Pazopanib has poor single agent activity in advanced anaplastic thyroid cancer.

Abstract 1278: Phase 1 study of CS-7017, an oral PPAR-γ agonist, in combination with paclitaxel in advanced anaplastic thyroid cancer

Abstract Background: Stage IVC (metastatic) anaplastic thyroid cancer (ATC) has a median overall survival (OS) of only 1.9 months. Single agent paclitaxel has modest activity in ATC. In pre-clinical studies, CS-7017 inhibited ATC proliferation through a novel mechanism–activation of PPAR-γ, followed by sequential upregulation of RhoB, then p21. Moreover, CS-7017 augmented the proapoptotic effects of paclitaxel. Based on these results, a multicenter study was conducted to determine if CS-7017+paclitaxel might prove safe and effective in advanced ATC. Design: A Phase 1 study was conducted to determine the Phase 2 dose. In Phase 1, patients received CS-7017 orally BID for one week (run-in phase), followed by a 3 h iv infusion of paclitaxel (175 mg/m2) every 3 weeks in combination with BID CS-7017. CS-7017 doses were escalated (0.15, 0.3, or 0.5 mg). Tissue biopsies were obtained at baseline and at one and three weeks for immunohistochemistry of PPAR-γ responsive proteins; serum CS-7017 PK studies were also performed. Results: Nineteen patients were enrolled, but 4 were not dosed (3 due to progression, 1 ineligible). Seven participated in CS-7017 dose levels 1a/1b (0.15 mg BID), six in dose level 2 (0.3 mg BID), and two in dose level 3 (run-in phase only–0.5 mg BID). Demographics: Of the 15 treated patients, 10 (67%) were women. Median age was 59 years (range: 43-82) Efficacy: Of 15 patients receiving drug, one had a confirmed partial response (PR) lasting from Day 69 to Day 175, and eight had stable disease (SD) as their best response. Median Time to Progression in 7 patients at Dose Level 1 was 49 days, but 70 days in Dose Level 2 (43% prolongation); corresponding median survival was 99 (0.15 mg BID) vs. 140 days (0.3 mg BID, 42% increase). Median peak CS-7017 blood level was 8.6 ng/mL (range: 5.1 to 13.7) for Level 1 and 22.0 ng/mL (17.0 to 31.5) for Dose Level 2. Adverse Events: Ten patients had AEs ≥ Grade 3, with two (anemia and localized edema) related to CS-7017. Thirteen events of fluid retention/edema were reported in 8 patients, with only 2 events of CTCAE grade ≥ 3. Eight patients had ≥ one SAE, with one (anemia) due to CS-7017. One SAE (anaphylactic reaction) was related to paclitaxel. No dose limiting toxicity was observed. Immunohistochemistry: Biopsies were available on 7 patients. PPAR-γ, RXR-α, RhoB were present in all; Angiopoietin-like 4 was induced by CS-7017. Conclusions: Combination therapy with CS-7017 and paclitaxel was tolerated and has biologic activity in patients with metastatic anaplastic thyroid carcinoma, with initial exploratory data suggesting a dose-dependent improvement in time to progression and survival in response to escalating CS-7017 dosage. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1278. doi:10.1158/1538-7445.AM2011-1278

A Phase II Study of Imatinib in Patients with Advanced Anaplastic Thyroid Cancer

Currently, there is no standard treatment for metastatic anaplastic thyroid cancer (ATC). DNA microarray analysis has shown platelet-dervived growth factor receptor (PDGFR) overexpression in ATC relative to well-differentiated thyroid cancer. In p53-mutated/deficient ATC cell lines, cABL is overexpressed, and selective inhibition of cABL results in a cytostatic effect. Imatinib inhibits tyrosine kinase activity of Bcr-ABL and PDGF. We hypothesize that patients with ATC that over-expresses PDGF receptors or cABL will respond to imatinib. Patients with histologically confirmed ATC who had measurable disease and whose disease expressed PDGF receptors by immunohistochemistry were eligible for study. Imatinib was administered at 400 mg orally twice daily without drug holiday. Response to treatment was assessed every 8 weeks. Patients with complete response, partial responses, or stable disease were treated until disease progression. The study was terminated early due to poor accrual. From February 2004 to May 2007, 11 patients were enrolled and were started on imatinib. At baseline, 4/11 had locoregional disease, 5/11 had distant metastases, and 2/11 had both. Nine of 11 had prior chemoradiation, and 7/11 had thyroidectomy. Eight of 11 were evaluable for response; 4 were excluded for lack of follow-up with radiologic evaluation. The overall response rates at 8 weeks were complete response 0/8, partial response 2/8, and stable disease 4/8. The median time to follow-up was 26 months (ranges 23-30 months). The rate of 6-month progression-free survival was 36% (95% confidence interval, 9%-65%). The rate of 6-month overall survival was 45% (95% confidence interval, 16%-70%). The most common grade 3 toxicity was edema in 25%; other grade 3 toxicities included fatigue and hyponatremia (12.5% each). There were no grade 4 toxicities or treatment related deaths. Imatinib appears to have activity in advanced ATC and is well tolerated. Due to difficulty of accruing patients with a rare malignancy at a single institution, further investigation of imatinib in ATC may be warranted in a multi-institutional setting.