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Molecular Drivers in Lung Adenocarcinoma: Therapeutic Implications
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Imayavaramban Lakshmanan, Apar Kishor Ganti
A variety of targeted agents against RET pathways has been studied in other malignancies. These include vandetanib, cabozantinib, sunitinib, sorafenib, fostamatinib and ponatinib with good response, especially in RET mutated tumors [73]. However, studies with RET inhibitors in NSCLC are lacking. Vandetanib has been shown to have some in vitro activity against cancer cells with RET rearrangements [74]. Gautschi et al. described a case of lung adenocarcinoma, positive for RET-KIF5B, where vandetanib was used at disease progression following chemotherapy, surgery and radiation, with the development of disease remission after four weeks of vandetanib treatment [78]. A prospective phase II trial studying the role of cabozantinib, a multi-tyrosine kinase inhibitor and a potent inhibitor of RET, in NSCLC patients with RET rearrangements also showed partial responses in two out of three cases and prolonged stable disease after eight months in the third case, with no progression of the disease reported in any of the three [77]. There are ongoing phase II trials to evaluate the efficacy of lenvatinib, vandetanib, and sunitinib in NSCLC with RET rearrangements [79].
Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Vandetanib (CaprelsaTM) is a small-molecule orally administered tyrosine kinase inhibitor approved by the FDA in 2011 for the treatment of late-stage thyroid cancer (Figure 6.25). It was initially evaluated in clinical trials for non-small-cell lung cancer although no benefit was observed when administered alongside chemotherapy. It is recommended by NICE in the UK for the treatment of aggressive and symptomatic medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease. Structure of vandetanib (Caprelsa™).
Systemic Therapy (Targeted Therapy and Immunotherapy) for Thyroid Cancers
Published in Madan Laxman Kapre, Thyroid Surgery, 2020
This MKI has been primarily researched in advanced MTCs. It targets RET, VEGFR, EGFR, and c-kit. Its efficacy was first demonstrated in a phase II trial of 30 advanced or metastatic hereditary MTCs. In this study, PR was achieved in 22 patients at a dose of vandetanib 300 mg per day [31]. This was followed by a phase III, randomized, placebo-controlled trial (ZETA trial). This trial included 331 patients with advanced MTC and showed a significantly better PFS with vandetanib as compared to the placebo group (30.5 months vs 19.3 months; HR 0.46; p = 0.001) [32]. The side effect profile included diarrhea, rash, nausea, and a rare but critical adverse effect in form of QT prolongation, potentially leading to torsades de pointes [32]. Subsequently, vandetanib became the first FDA-approved drug for treatment of unresectable, locally advanced or metastatic MTC. Although not approved for RAI-refractory DTC, vandetanib has been tested in a phase II randomized trial in this group of patients. Here it was found to have a good efficacy with an improvement in PFS in those receiving the drug over the placebo group (median PFS 11.1 months vs 5.9 months; HR 0.63; p = 0.008) [33]. Vandetanib is currently being studied in a phase III, randomized trial of 238 patients with advanced RAI-refractory thyroid cancers (VERIFY trial, NCT01876784). The results of this trial are being awaited at the time of writing this chapter.
Emerging tyrosine kinase inhibitors for head and neck cancer
Published in Expert Opinion on Emerging Drugs, 2022
Zhen Long, Jennifer R. Grandis, Daniel E. Johnson
Vandetanib (Caprelsa) is an oral multi-targeted TKI that inhibits VEGFR-2, HER1 (EGFR), and RET [107–109]. Vandetanib has been approved by the FDA for use in advanced medullary thyroid cancer. In HNSCC preclinical models vandetanib has been shown to enhance anti-cancer effects in vitro and in vivo when used in combination with cisplatin, radiation, or photodynamic therapy [110–112]. Although a Phase I study of vandetanib plus radiation in patients with locally advanced HNSCC demonstrated tolerability of the treatment regimen [113], a study of vandetanib in combination with cisplatin/radiation (NCT00720083) was terminated early (withdrawal of drug), while a Phase II study of vandetanib plus docetaxel (NCT00459043) yielded unremarkable improvement in PFS [114]. A placebo-controlled trial of vandetanib as a chemopreventive agent in patients with premalignant lesions has recently been completed and awaits publication (NCT01414426).
The Risk of QTc Prolongation in Non-Diabetic and Diabetic Patients Taking Tyrosine Kinase Inhibitors (TKIs)- A Patient Safety Project at a Private Oncology Practice
Published in Journal of Community Hospital Internal Medicine Perspectives, 2021
Zhongju Lu, Ying Luu, Jack Ip, Imran Husain, Michael Lu, Chang-Kyung Kim, Peng Yang, David Chu, Richard Lin, Ira Cohen, Alan Kaell
Among the TKIs, nilotinib, vandetanib, and sunitinib are frequently reported for their QT prolonging effects [19]. Increased risk of QT prolongation is associated with higher doses of vandetanib, usually within three months of treatment [25]. Similarly, within the clinic, sunitinib has been reported to exhibit dose-dependent cardiovascular-related adverse events, including QT prolongation [31]. In comparison, the QTc prolongation is prevalent among TKIs tested in our study and Eriotinib, Palbociclib, Sorafenib, Ruxolitinib demonstrated significantly higher prevalence of severe QTc prolongation and absolute QTc intervals. Given the prevalence of diabetes and increased use of TKIs for cancer treatment, our findings that TKIs cause a significantly higher prevalence of QT prolongation, which was further augmented in diabetic patients, brings clinical concern for TKIs use in diabetes.
Organotypic tumor slice cultures provide a versatile platform for immuno-oncology and drug discovery
Published in OncoImmunology, 2019
Ramya Sivakumar, Marina Chan, Jiye Stella Shin, Nao Nishida-Aoki, Heidi L. Kenerson, Olivier Elemento, Himisha Beltran, Raymond Yeung, Taranjit S. Gujral
Comparison with organoid models revealed that the most drugs exhibited the same effect or lack thereof in both organoid and tumor slice models (Figure 6(e)). However, tumor slice cultures were more sensitive to vandetanib, and dabrafenib; whereas organoids were more sensitive to teniposide and topotecan (Figure 6(e)). We predict that the differences in sensitivity between the two models relate to differences in cell populations or biophysical differences, such as the stiffness of the extracellular matrix and strength of cellular attachments. For example, treatment of colon PDX slices with vandetanib (2 μM) significantly decreased overall slice viability (Figure 6(d,e)), whereas this drug had no effect on the growth of the organoid culture (Figure 6(e)). Vandetanib is a VEGFR inhibitor that inhibits angiogenesis.42 The difference in toxicity between the PDX tissue slices and the organoid may result from the presence of endothelial cells and blood vessels only in the tissue slice system. Thus, by targeting endothelial cells in the tumor slices, vandetanib resulted in reduced viability of the cells in the PDX tumor slice preparation. These data suggested that organoids and tumor tissue cultures from the same tumor are not equivalent with regard to their pharmacological profiles.