Novel targeted therapies and immunotherapy for advanced thyroid cancers

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Abstract

Thyroid cancer is a frequently encountered endocrine malignancy. Despite the favorable prognosis of this disease, 15–20% of differentiated thyroid cancer (DTC) cases and most anaplastic types, remain resistant to standard treatment options, including radioactive iodine (RAI). In addition, around 30% of medullary thyroid cancer (MTC) cases show resistance after surgery. The evolving understanding of disease-specific molecular therapeutic targets has led to the approval of two targeted therapies (Sorafenib and Lenvatinib) for RAI refractory DTC and another two drugs (Vandetanib and Cabozantinib) for MTC. These advanced therapies exert their effects by blocking the MAPK pathway, which has been widely correlated to different types of thyroid cancers. While these drugs remain reserved for thyroid cancer patients who failed all treatment options, their ability to improve patients’ overall survival remain hindered by their low efficacy and other molecular factors. Among these factors is the tumor’s ability to activate parallel proliferative signaling pathways other than the cascades blocked by these drugs, along with overexpression of some tyrosine kinase receptors (TKR). These facts urge the search for novel different treatment strategies for advanced thyroid cases beyond these drugs. Furthermore, the growing knowledge of the dynamic immune system interaction with tumor microenvironment has revolutionized the cancer immune therapy field. In this review, we aim to discuss the molecular escape mechanisms of thyroid tumors from these drugs. We also highlight novel therapeutic options targeting other pathways than MAPK, including PI3K pathway, ALK translocations and HER2/3 receptors and their clinical impact. We also aim to discuss the usage of targeted therapy in restoring thyroid tumor sensitivity to RAI, and finally turn to extensively discuss the role of immunotherapy as a potential alternative treatment option for advanced thyroid diseases.

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The online version of this article (10.1186/s12943-018-0786-0) contains supplementary material, which is available to authorized users.

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Cancer immunotherapy: the beginning of the end of cancer?

Sofia Farkona, Eleftherios P. Diamandis, Ivan M Blasutig (2016)

These are exciting times for cancer immunotherapy. After many years of disappointing results, the tide has finally changed and immunotherapy has become a clinically validated treatment for many cancers. Immunotherapeutic strategies include cancer vaccines, oncolytic viruses, adoptive transfer of ex vivo activated T and natural killer cells, and administration of antibodies or recombinant proteins that either costimulate cells or block the so-called immune checkpoint pathways. The recent success of several immunotherapeutic regimes, such as monoclonal antibody blocking of cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD1), has boosted the development of this treatment modality, with the consequence that new therapeutic targets and schemes which combine various immunological agents are now being described at a breathtaking pace. In this review, we outline some of the main strategies in cancer immunotherapy (cancer vaccines, adoptive cellular immunotherapy, immune checkpoint blockade, and oncolytic viruses) and discuss the progress in the synergistic design of immune-targeting combination therapies.

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Molecular genetics and diagnosis of thyroid cancer.

Yuri E. Nikiforov, Marina Nikiforova (2011)

Thyroid cancer is a common type of endocrine malignancy, and its incidence has been steadily increasing in many regions of the world. Initiation and progression of thyroid cancer involves multiple genetic and epigenetic alterations, of which mutations leading to the activation of the MAPK and PI3K-AKT signaling pathways are crucial. Common mutations found in thyroid cancer are point mutation of the BRAF and RAS genes as well as RET/PTC and PAX8/PPARγ chromosomal rearrangements. The mutational mechanisms seem to be linked to specific etiologic factors. Chromosomal rearrangements have a strong association with exposure to ionizing radiation and possibly with DNA fragility, whereas point mutations probably arise as a result of chemical mutagenesis. A potential role of dietary iodine excess in the generation of BRAF point mutations has also been proposed. Somatic mutations and other molecular alterations have been recognized as helpful diagnostic and prognostic markers for thyroid cancer and are beginning to be introduced into clinical practice, to offer a valuable tool for the management of patients with thyroid nodules.

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The mTOR Signalling Pathway in Human Cancer

Helena Pópulo, José Manuel Lopes, Paula Soares (2012)

The conserved serine/threonine kinase mTOR (the mammalian target of rapamycin), a downstream effector of the PI3K/AKT pathway, forms two distinct multiprotein complexes: mTORC1 and mTORC2. mTORC1 is sensitive to rapamycin, activates S6K1 and 4EBP1, which are involved in mRNA translation. It is activated by diverse stimuli, such as growth factors, nutrients, energy and stress signals, and essential signalling pathways, such as PI3K, MAPK and AMPK, in order to control cell growth, proliferation and survival. mTORC2 is considered resistant to rapamycin and is generally insensitive to nutrients and energy signals. It activates PKC-α and AKT and regulates the actin cytoskeleton. Deregulation of multiple elements of the mTOR pathway (PI3K amplification/mutation, PTEN loss of function, AKT overexpression, and S6K1, 4EBP1 and eIF4E overexpression) has been reported in many types of cancers, particularly in melanoma, where alterations in major components of the mTOR pathway were reported to have significant effects on tumour progression. Therefore, mTOR is an appealing therapeutic target and mTOR inhibitors, including the rapamycin analogues deforolimus, everolimus and temsirolimus, are submitted to clinical trials for treating multiple cancers, alone or in combination with inhibitors of other pathways. Importantly, temsirolimus and everolimus were recently approved by the FDA for the treatment of renal cell carcinoma, PNET and giant cell astrocytoma. Small molecules that inhibit mTOR kinase activity and dual PI3K-mTOR inhibitors are also being developed. In this review, we aim to survey relevant research, the molecular mechanisms of signalling, including upstream activation and downstream effectors, and the role of mTOR in cancer, mainly in melanoma.

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Author and article information

Contributors

George E. Naoum: 857-238-6475 , gnaoum@mgh.harvard.edu

Michael Morkos: 312-864-0540 , Michael_G_Morkos@rush.edu

Brian Kim: 312 942-3189 , Brian_W_Kim@rush.edu

Waleed Arafat: 781-666-7780 , w.o.arafaat@gmail.com

Journal

Journal ID (nlm-ta): Mol Cancer

Journal ID (iso-abbrev): Mol. Cancer

Title: Molecular Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 1476-4598

Publication date (Electronic): 19 February 2018

Publication date PMC-release: 19 February 2018

Publication date Collection: 2018

Volume: 17

Electronic Location Identifier: 51

Affiliations

[1 ]Department of Radiation Oncology, Harvard Medical School, Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114 USA

[2 ]Alexandria Comprehensive Cancer center, Alexandria, Egypt

[3 ]ISNI 0000000107058297, GRID grid.262743.6, Department of Endocrinology, , Rush University, ; 1900 W Polk St, Room 801, Chicago, IL USA

[4 ]Department of Endocrinology, Thyroid Cancer Program, Rush University, Jelke Building, Room 604, 1735 W Harrison St, Chicago, IL 60612 UK

[5 ]ISNI 0000 0001 2260 6941, GRID grid.7155.6, University Of Alexandria, Clinical oncology department, ; Alexandria, Egypt

[6 ]Department of Radiation Oncology, University of Alabama at Birmingham, 1720 2nd Ave S, Birmingham, AL 35294 UK

Article

Publisher ID: 786

DOI: 10.1186/s12943-018-0786-0

PMC ID: 5817719

PubMed ID: 29455653

SO-VID: 4f224426-8580-405c-b39d-8efb62112bd6

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 19 September 2017

Date accepted : 1 February 2018

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ScienceOpen disciplines: Oncology & Radiotherapy

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ScienceOpen disciplines: Oncology & Radiotherapy

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Novel targeted therapies and immunotherapy for advanced thyroid cancers

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Cancer Immunotherapy

Most cited references 125

Cancer immunotherapy: the beginning of the end of cancer?

Molecular genetics and diagnosis of thyroid cancer.

The mTOR Signalling Pathway in Human Cancer

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Cited by 102

Most referenced authors 2,594