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Aggressive endocrine tumors – targeted therapy with kinase inhibitors

Posted in Advanced Drug Manufacturing Technology, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Prevention: Research & Programs, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Molecular Genetics & Pharmaceutical, Population Health Management, Genetics & Pharmaceutical, tagged , , , , on June 10, 2013| 1 Comment »

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

Abbreviations:

 

Kinase inhibitors (KIs)

Adenosine triphosphate (ATP)

Mitogen-activated protein kinases (MAPK)

Tyrosine kinase (TK)

Papillary thyroid carcinomas (PTC)

Radioiodine (RAI)

Medullary thyroid carcinoma (MTC)

Mammalian target of rapamycin (mTOR)

Neuroendocrine tumors (NETs)

Adrenocortical carcinoma (ACC)

Kinase inhibitors (KIs) are a group of small organic molecules that interfere with the interaction between the kinase domain and adenosine triphosphate (ATP) or other mechanisms such as allosteric inhibitors, thereby inhibiting phosphorylation of the kinase and activation of downstream signaling pathways. The majority of KIs available in clinical practice are non-selective, being active against several molecular targets. They exhibit anticancer activity by targeting molecules that activate signalling pathways which promote cellular survival, proliferation and growth. Besides, KIs act as anti-angiogenic agents by halting the activation of specific receptors of angiogenic factors, thus inhibiting intracellular pathways that stimulate angiogenesis. In the last 15 years, several KIs have been developed and introduced into anticancer clinical trials. Aggressive forms of endocrine cancer are not uniformly responsive to cytotoxic chemotherapies while radiotherapy has mainly a palliative role. To date, therapeutic approach of endocrine tumors which persist after surgery and are not responsive to cytotoxic chemotherapies is challenging. Treatment with KIs is gaining a growing role in this clinical context. The present review focuses state-of-theart role of KIs for the treatment of advanced endocrine neoplasms. The protein kinases transfer the g-phosphate of ATP to the hydroxyl group of a serine, threonine or tyrosine residue on a target protein. Phosphorylation results in a number of diverse conformational and/or functional modifications in different proteins, thus initiating a downstream cascade of reactions. Thereby, the protein kinases act as effectors of intracellular cascades, such as the mitogen-activated protein kinases (MAPK) and the PI3K/Akt pathways, which regulate crucial cellular processes including proliferation, differentiation and survival. Abnormal activation of these pathways is strikingly involved in the process of human oncogenesis. Moreover, activity of angiogenic factors with a demonstrated role in survival and spread of cancer cells are mediated by receptors with tyrosine kinase (TK) function. To date, treatment with KIs is considered the most promising frontier in the field of oncology, especially in cases where the role of a particular protein kinase has a direct causal relevance to cancer through its inappropriate activation. Activating mutations of protein kinases genes have been associated with several types of endocrine cancer. About 70% of papillary thyroid carcinomas (PTC), the most common type (80-85%) of thyroid cancer, arise as a result of single activating somatic mutations of protein kinases genes. These involve single point mutations of BRAF and RAS and rearrangements of RET named RET/ PTC oncogenes. Furthermore, BRAF mutations are associated with radioiodine (RAI) unresponsiveness and increased rates of disease recurrence and mortality. The prominent role of the protein kinase RET in the pathogenesis of medullary thyroid carcinoma (MTC) has been widely demonstrated. RET proto-oncogene encodes a cell membrane TK receptor which regulates activation of the MAPK and PI3K/Akt pathways. Germline RET point mutations are responsible of hereditary forms of MTC, while approximately 50% of sporadic MTCs harbor activating RET mutations. Furthermore, there is a clear correlation between genotype and tumor behavior. A recent study performed by Moura et al. demonstrated that the majority of sporadic RET-negative MTC harbor mutations of HRAS, thus confirming that abnormal activation of the MAPK and PI3K/Akt pathways is a crucial step for MTC tumorigenesis. The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that plays an important role in cellular growth and homeostasis. mTOR is activated by both phosphorylation through PI3K/Akt pathway and autophosphorylation at specific serine residues. As hyperactivation of the mTOR pathway has been detected in many human cancers, mTOR has become one of the most promising targets in anticancer therapy. Recent studies found that mTOR pathway is involved in the pathogenesis of neuroendocrine tumors (NETs) and adrenocortical carcinoma (ACC), thus stimulating trials with selective mTOR inhibitors for the treatment of these endocrine cancers.

Several retrospective and Phase II studies have been published about efficacy and safety of KIs in endocrine cancer but only few randomized Phase III clinical trials have been completed. To date, the largest experience has been gained in the treatment of advanced forms of MTC and NETs. Vandetanib and cabozantinib have been recently approved by the FDA for the treatment of advanced, progressive MTC. Given the toxicity related to the long-term administration, some authors suggest a selective use of these compounds in MTC patients having a wide disease burden and/or a strong progression of disease. Nevertheless, MTC usually exhibits an indolent behavior with just a slow progression of disease even in metastatic patients. Therefore, further studies are needed to identify therapeutic approaches which could improve the risk/benefit ratio in this kind of patients. Treatment with the mTOR inhibitor everolimus, alone or in combination with somatostatin analogs, should be considered in this field. In 2011, sunitinib and everolimus have been definitively approved for the treatment of advanced pancreatic NET. Given the slowly progressing nature of NET, even in advanced cases, patients are likely to be treated with these agents for many months and possibly years. Therefore, issues of long-term safety and compliance will require special attention in the future. Unfortunately, lack of available comparative studies between these targeted therapies makes it difficult to suggest the optimal sequence of treatments. Currently, treatment with TKIs represents the only feasible approach in patients with advanced RAI-refractory DTC. Nevertheless, none of these agents has been approved yet. Two randomized Phase III clinical trials evaluating activity of sorafenib and lenvatinib have recently completed patient accrual, but results are not available yet. Use of KIs has shown promising but still anecdotal results in the treatment of other types of endocrine cancers such as ATC, PGL/PCC and ACC and Phase II/III trials are needed to assess feasibility and activity of KIs in these fields. Finally, a better understanding of the molecular pathogenesis of other endocrine malignancies such as aggressive pituitary tumors and parathyroid carcinoma would be crucial for providing the rationale to the use of KIs.

Source References:

http://www.ncbi.nlm.nih.gov/pubmed/23675883

http://www.ncbi.nlm.nih.gov/pubmed/23450053

http://www.ncbi.nlm.nih.gov/pubmed/17993229

http://www.ncbi.nlm.nih.gov/pubmed/17253488

http://www.ncbi.nlm.nih.gov/pubmed/20605972

http://www.ncbi.nlm.nih.gov/pubmed/10387987

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