Lenvatinib plus Anti-PD-1 Combination Therapy for Advanced Cancers: Defining Mechanisms of Resistance in an Inducible Transgenic Model of Thyroid Cancer

Context. Anaplastic thyroid cancer (ATC) is an aggressive tumor with a median survival of 3 to 9 months, a 1-year survival of less than 10% and without definitive therapies. Recently, in BRAF V600E mutated ATCs, new targeted therapy using a combination of a BRAF inhibitor, dabrafenib (Dab), with a mitogen-activated extracellular protein kinase (MEK) inhibitor, trametinib (Tram), has shown significant promise. Case Description. We report a case of aggressive ATC with 5 sequence mutations: BRAF V600E (mutation fraction [MF] 34%), TERT E441del (MF 37%), RET N579K (MF 55%), EZH2 D154E (MF 60%), and CDK4 S259L (MF 48%). The patient had a dramatic response to the Dab/Tram combination with near complete resolution of his lung, bone, hepatic, and splenic lesions soon after starting therapy. Unfortunately, intolerable side effects (grade 2-3) on this regimen required tapering and discontinuation of the treatment. He had a quick resurgence of disease after stopping the combination therapy. The patient died approximately 3 months after discontinuing Dab/Tram. Autopsy revealed an atrophic thyroid gland with microscopic subcapsular focus of well-differentiated papillary thyroid carcinoma. There was extensive lymphatic spread of the tumor throughout bilateral lungs with fibrosis. No other metastatic site was identified. Conclusion. We report a unique case of ATC with 2 new mutations of EZH2 D154E and CDK S529L. This case exemplifies the significant promise Dab/Tram therapy holds, the potential side effects that limit their use, and autopsy findings status post use of this combination therapy.

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Lenvatinib Promotes the Antitumor Effects of Doxorubicin in Anaplastic Thyroid Cancer

10.21203/rs.3.rs-29005/v1 ◽

2020 ◽

Author(s):

Xi Su ◽

Jiaxin Liu ◽

Haihong Zhang ◽

Qingqing Gu ◽

Xinrui Zhou ◽

...

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Thyroid Cancer ◽

Combination Therapy ◽

Cell Cycle Arrest ◽

Anaplastic Thyroid Cancer ◽

Antitumor Efficacy ◽

Potential Candidate ◽

Antitumor Effects ◽

Cycle Arrest

Abstract Background Anaplastic thyroid cancer (ATC) is a kind of rare thyroid cancer with very poor prognosis. It is one of the deadliest cancers in human due to the aggressive behavior and resistance to treatment. Doxorubicin has been approved in ATC treatment as a single agent, but monotherapy still shows no improvement of the total survival in advanced ATC. Lenvatinib was investigated with encouraging results in treating the patients with radioiodine-refractory differentiated thyroid cancer (DTC). However, antitumor efficacy of combination therapy with lenvatinib and doxorubicin remains largely unclear. Methods The antitumor efficacy of combination therapy with lenvatinib and doxorubicin on ATC cell proliferation and was assessed by the MTT assay and colony formation. Flow cytometry were employed to assess ATC cells’ apoptosis and cell cycle arrest in response to combination therapy. Xenograft models were used to test its in vivo antitumor activity. Result Lenvatinib monotherapy was less effective than doxorubicin in treating ATC cell lines and xenografts model. The combination therapy of lenvatinib and doxorubicin significantly inhibited ATC cell proliferation and tumor growth in nude mice, and induced cell apoptosis and cell cycle arrest in compared to lenvatinib or doxorubicin monotherapy. Conclusion Lenvatinib promotes the antitumor effects of doxorubicin in ATC cell and xenografts model. Lenvatinib/doxorubicin combination may be a potential candidate therapeutic approach for ATC.

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New Horizons: Emerging Therapies and Targets in Thyroid Cancer

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa687 ◽

2020 ◽

Vol 106 (1) ◽

pp. e382-e388

Author(s):

Matthew D Ringel

Keyword(s):

Thyroid Cancer ◽

Disease Process ◽

Therapeutic Strategies ◽

Mechanisms Of Resistance ◽

New Horizons ◽

Therapeutic Modalities ◽

Emerging Therapies ◽

Improve Patient Selection ◽

Selection For ◽

Improve Patient

Abstract The treatment of patients with progressive metastatic follicular cell-derived and medullary thyroid cancers that do not respond to standard therapeutic modalities presents a therapeutic challenge. As a deeper understanding of the molecular drivers for these tumors has occurred and more potent and specific compounds are developed, the number of Food and Drug Administration (FDA)-approved treatments for thyroid cancer has expanded. In addition, with the advent of disease-agnostic target-directed FDA approvals an ever-broadening number of therapeutic options are available for clinicians and patients. However, to date, complete remissions are rare, the average durations of response are relatively modest, and toxicities are common. These factors accentuate the need for further understanding of the mechanisms of resistance that result in treatment failures, the development of biomarkers that can improve patient selection for treatment earlier in the disease process, and the continued need for new therapeutic strategies. In this article, recent approvals relevant to thyroid cancer will be discussed along with selected new potential avenues that might be exploited for future therapies.

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Mechanisms of resistance to Erbitux (anti?epidermal growth factor receptor) combination therapy in pancreatic adenocarcinoma cells

Journal of Gastrointestinal Surgery ◽

10.1016/j.gassur.2004.09.021 ◽

2004 ◽

Vol 8 (8) ◽

pp. 960-970 ◽

Cited By ~ 34

Author(s):

J ARNOLETTI ◽

D BUCHSBAUM ◽

Z HUANG ◽

A HAWKINS ◽

M KHAZAELI ◽

...

Keyword(s):

Epidermal Growth Factor Receptor ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Combination Therapy ◽

Pancreatic Adenocarcinoma ◽

Growth Factor Receptor ◽

Mechanisms Of Resistance ◽

Adenocarcinoma Cells ◽

Epidermal Growth

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Vitamin C sensitizes BRAFV600E thyroid cancer to PLX4032 via inhibiting the feedback activation of MAPK/ERK signal by PLX4032

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-01831-y ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Xi Su ◽

Peng Li ◽

Bin Han ◽

Hao Jia ◽

Qingzhuang Liang ◽

...

Keyword(s):

Cell Cycle ◽

Thyroid Cancer ◽

Combination Therapy ◽

Vitamin C ◽

Cancer Cell ◽

Antitumor Effect ◽

Akt Pathway ◽

Thyroid Cancer Cell ◽

Cycle Arrest ◽

Feedback Activation

Abstract Background BRAFV600E mutation is the most common mutation in thyroid cancer. It strongly activates MAPK/ERK pathway and indicates an invasive subtype of thyroid cancer. PLX4032 is a selective oral inhibitor of the BRAFV600 kinase although with limited effect in treating this panel of thyroid cancer, due to the feedback activation of MAPK/ERK as well as PI3K/AKT pathways. It was investigated that Vitamin C plays a positive role in inhibiting these pathways in thyroid cancer. However, whether Vitamin C could enhance the antitumor effect of PLX4032 remains largely unclear. Methods The antitumor efficacy of combination therapy with PLX4032 and Vitamin C on BRAFMT thyroid cancer cell was assessed by the MTT assay, EdU assay and colony formation, Chou-Talalay way was employed to analyze the synergistic effect. Flow cytometry were employed to assess cells’ apoptosis and cell cycle arrest in response to combination therapy. Xenograft models were used to test its in vivo antitumor activity. Western blot and IHC were applied to investigate the mechanism underlying synergistic effect. Results PLX4032 or Vitamin C monotherapy was mildly effective in treating BRAFMT thyroid cancer cell and xenografts model. The combination therapy significantly inhibited cancer cell proliferation and tumor growth in nude mice, and induced cell apoptosis and cell cycle arrest compared to either monotherapy. PLX4032 monotherapy induced feedback activation of MAPK/ERK as well as PI3K/AKT pathway; while combination therapy significantly relieved this feedback. Conclusion Vitamin C promotes the antitumor effect of PLX4032 in BRAFMT thyroid cancer cell and xenografts model via relieving the feedback activation of MAPK/ERK as well as PI3K/AKT pathway. PLX4032/Vitamin C combination may be a potential therapeutic approach to treat BRAFMT thyroid cancer.

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Targeting the NF-κB Pathway as a Combination Therapy for Advanced Thyroid Cancer

PLoS ONE ◽

10.1371/journal.pone.0134901 ◽

2015 ◽

Vol 10 (8) ◽

pp. e0134901 ◽

Cited By ~ 18

Author(s):

Nikita Pozdeyev ◽

Adam Berlinberg ◽

Qiong Zhou ◽

Kelsey Wuensch ◽

Hiroyuki Shibata ◽

...

Keyword(s):

Thyroid Cancer ◽

Combination Therapy ◽

Advanced Thyroid Cancer

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Synergistic Anticancer Activity of N-Hydroxy-7-(2-Naphthylthio) Heptanomide, Sorafenib, and Radiation Therapy in Patient-Derived Anaplastic Thyroid Cancer Models

International Journal of Molecular Sciences ◽

10.3390/ijms22020536 ◽

2021 ◽

Vol 22 (2) ◽

pp. 536

Author(s):

Hyeok Jun Yun ◽

Hee Jun Kim ◽

Jungmin Kim ◽

Sang Yong Kim ◽

Hang-Seok Chang ◽

...

Keyword(s):

Cell Cycle ◽

Radiation Therapy ◽

Thyroid Cancer ◽

Combination Therapy ◽

Intracellular Signaling ◽

Xenograft Model ◽

Anaplastic Thyroid Cancer ◽

Anticancer Effect ◽

Mouse Xenograft Model

Anaplastic thyroid cancer (ATC) is an undifferentiated and advanced form of thyroid cancer, accompanied with a high ratio of epigenetic adjustment, which occurs more than genetic mutations. In this study, we aimed to evaluate the synergistic anticancer effect (in vitro and in vivo) of the new combination of N-hydroxy-7-(2-naphthylthio) heptanomide (HNHA) and sorafenib with radiation therapy in pre-clinical models of ATC. The ATC cell lines, YUMC-A1 and YUMC-A2, were isolated from the current patients who were treated with HNHA and sorafenib, either as monotherapy or combination therapy. Synergistic anticancer effect of the combination therapy on the intracellular signaling pathways and cell cycle was assessed via flow cytometry and immunoblot analysis. To examine tumor shrinkage activity in vivo, an ATC cell line-derived mouse xenograft model was used. Results showed that the combination therapy of HNHA and sorafenib with radiation promoted tumor suppression via caspase cleavage and cell cycle arrest in patient-derived ATC. In addition, the combination therapy of HNHA and sorafenib with radiation was more effective against ATC than therapy with HNHA or sorafenib with radiation. Thus, the combination of HNHA and sorafenib with radiation may be used as a novel curative approach for the treatment of ATC.

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