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Therapeutic Options for Prostate Cancer: A Contemporary Update
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Sakthivel Muniyan, Jawed A. Siddiqui, Surinder K. Batra
Bone metastasis is the characteristic clinical symptom for patients with CRPCa and has a negative impact on prognosis. Most of the chemotherapy and RT to treat PCa and bone metastasis are mainly palliative. It has been reported that approved standard localized PCa therapies, abiraterone (CYP17 inhibitor) and enzalutamide (AR antagonist) both have demonstrated to significantly delay the SREs in patients with mCRPC [28, 131]. The outcome of a recent clinical trial suggests that cabozantinib (a tyrosine kinase inhibitor) improves the skeletal health in mCRPC [132]. The exact mechanism by which cabozantinib reduces the SREs is not explored, but it may target both cancer cells and osteoblasts [132]. However, direct bone-targeted therapies have a significant advantage for patients with PCa bone metastasis. In past years, advances in the understanding of the molecular mechanism of bone metastasis and cancer cell-bone microenvironment interactions have allowed the development of new targets and therapeutic agents to treat bone metastasis (Table 1).
Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Multiple side effects have been observed for cabozantinib, including serious GI disturbances (e.g., gastric fistulas and abdominal pain), anxiety, fungal infections, hyperbilirubinemia, hyperkeratosis, hypoalbuminemia, palmar-plantar, erythrodysaesthesia syndrome, and impaired wound healing. In the US cabozantinib carries a black box warning of the risk of fistulas (i.e., holes) forming in the stomach or intestines, as well as between the GI tract and the skin). The black box warning also advises of the risk of uncontrolled bleeding.
EML4-ALK Fusion Gene and Therapy with ALK-Targeted Agents in Non-Small Cell Lung Cancer
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Francisco E. Vera-Badillo, Janet E. Dancey
Significant research activity is ongoing to identify effected therapies for patients with ALK and ROS mutation-positive NSCLC. With the advent of immunotherapy, formal trials to assess the role of immunotherapy in ALK and ROS1-positive tumors after TKI failure are underway. (NCT04042558, NCT03242915). TKIs in combination with antiangiogenic drugs and also other combinations are being explored (NCT03779191). For patients with surgically resected and ALK mutation-positive NSCLC, crizotinib is being explored as an adjuvant therapy (NCT02201992). Cabozantinib, a drug approved in renal cell carcinoma, is being explored in ROS1-mutation positive NSCLC (NCT01639508). Trials of experimental drugs will be reported out in the next few years. Trials assessing different techniques for the identification of tumor alterations are also ongoing with the aim of improving both diagnosis and treatment for these patients.
Tailoring treatment with cabozantinib or pazopanib in patients with metastatic renal cell carcinoma: does it affect outcome?
Published in Expert Review of Anticancer Therapy, 2023
Matilde Corianò, Diana Giannarelli, Giulia Scartabellati, Ugo De Giorgi, Nicole Brighi, Giuseppe Fornarini, Chiara Tommasi, Giulia Claire Giudice, Sara Elena Rebuzzi, Silvia Puglisi, Orazio Caffo, Stefania Kinspergher, Alessia Mennitto, Carlo Cattrini, Matteo Santoni, Elena Verzoni, Alessandro Rametta, Marco Stellato, Andrea Malgeri, Giandomenico Roviello, Matteo Brunelli, Alessio Signori, Giuseppe Luigi Banna, Sebastiano Buti
Likewise, cabozantinib, approved for patients with mRCC at the dose of 60 mg given orally once daily [35], has been proven to give the same outcomes in terms of PFS and OS in patients with an average cabozantinib trough concentration (Cmin) ≥750 ng/mL and patients with an average Cmin<750 ng/mL. Cabozantinib 40 mg once daily dose was then suggested as the most appropriate starting dose given its tolerability and maintained outcomes [17]. This is indeed the cabozantinib dose used in combination with immunotherapy [8]. Some data in the literature about the association between outcomes of patients affected by mRCC treated with reduced dose of cabozantinib are already available; moreover, toxicities were associated with higher drug exposure and inefficacy with lower drug exposure [17,36–38].
ROS1-positive non-small cell lung cancer (NSCLC): biology, diagnostics, therapeutics and resistance
Published in Journal of Drug Targeting, 2022
Zhi-Qiong Yu, Meng Wang, Wen Zhou, Meng-Xia Mao, Yuan-Yuan Chen, Na Li, Xiao-Chun Peng, Jun Cai, Zhi-Qiang Cai
Cabozantinib is a multi-targeted small molecule TKI of MET, AXL, VEGFR2, RET, KIT and ROS1, and its antitumor activity has been shown in various tumour types [108]. The combination of cabozantinib and gefitinib effectively inhibited the growth of ROS1-resistant tumours in an in vivo xenograft model in mice [109]. In cell-resistant models, ROS1 L2086F, ROS1 G2032R/L2086F and ROS1 S1986F/G2032R/L2086F were ineffective against lorlatinib but sensitive to cabozantinib. In a Japanese Phase 1 study (NCT01553656), cabozantinib was observed to shrink tumours in patients with NSCLC, including ALK-positive [108]. Four patients with crizotinib-resistant and ceritinib-resistant NSCLC received 100% disease control with cabozantinib, with a 25% objective response rate and PFS ranging from 4.9 to 13.8 months [110]. Cabozantinib may be another treatment drug after the first and second-generation ROS1 TKI resistance. Cabozantinib negative effects were more significant, with pneumonia (7%) and dehydration (5%) being the most serious; fatigue (13%), palmar-plantar erythema (10%), hypertension (7%), diarrhoea (7%) and weakness (5%) were the most prevalent grade 3/4 side effects. There was also one occurrence of bleeding grade 5 adverse event [111].
Effects of multi-kinase inhibitors on the activity of cytochrome P450 2J2
Published in Xenobiotica, 2022
Ayaka Kojima, Masayuki Nadai, Norie Murayama, Hiroshi Yamazaki, Miki Katoh
CYP2J2 protein is detected in all specimens of five types of gastric carcinoma and 10 of hepatocellular carcinoma (Jiang et al. 2009). CYP2J2 expression in hepatocellular carcinoma cell lines, HepG2 and Huh-7, is higher than that in normal liver epithelial cell line LO2 and the levels of 14,15-EET in HepG2 and Huh-7 were higher relative to those in LO2 cells (Gui et al. 2020). The treatment with a CYP2J2 inhibitor, acetylshikonin, inhibited the growth of HepG2 cells (Park et al. 2017) and the inhibition of CYP2J2 by tanshinone IIA induced apoptotic cell death in these cells (Jeon et al. 2015). Cabozantinib, which exhibits CYP2J2 inhibition by more than 50% as compared to the control (Figure 1), is approved in USA, EU, and Japan. Cabozantinib is used to treat patients with advanced renal cell carcinoma, hepatocellular carcinoma, and differentiated thyroid carcinoma. Elevated levels of CYP2J2 expression are the most significant in kidney cancer among other tumours (Zou and Mo 2021). CYP2J2 inhibition by acetylshikonin is associated with acetylshikonin-induced apoptosis in renal cell carcinoma (Lim et al. 2022). Therefore, CYP2J2 inhibition may be a plausible mechanism for apoptotic cell death in CYP2J2-overexpressing cancer cells.