Cabozantinib combination therapy for the treatment of solid tumors: a systematic review

Castellano, Daniel; Apolo, Andrea B.; Porta, Camillo; Capdevila, Jaume; Viteri, Santiago; Rodríguez‐Antona, Cristina; Martin, Lidia; Maroto, Pablo

doi:10.1177/17588359221108691

Cited by 4 publications

(1 citation statement)

References 81 publications

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“…The combination of novel anti-PD-L1 antibodies such as atezolizumab with novel anti-CTLA4 agents such as cabozantinib is also being tested in phase 3 clinical trials (NCT04446117), in CRPC patients previously treated with abiraterone or enzalutamide [78,165]. Clinical trials that test the efficacy of pembrolizumab with enzalutamide are recruiting patients with advanced hormonal-sensitive PCa (KEYNOTE-991: NCT04191096) and metastatic CRPC (KEYNOTE-641: NCT03834493) [26].…”

Section: Future Therapeutic Perspectives and Emerging Biomarkersmentioning

confidence: 99%

DNA Damage Repair Pathways in Prostate Cancer: A Narrative Review of Molecular Mechanisms, Emerging Biomarkers and Therapeutic Targets in Precision Oncology

Grypari

Tzelepi

Gyftopoulos

2023

IJMS

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Prostate cancer (PCa) has a distinct molecular signature, including characteristic chromosomal translocations, gene deletions and defective DNA damage repair mechanisms. One crucial pathway involved is homologous recombination deficiency (HRD) and it is found in almost 20% of metastatic castrate-resistant PCa (mCRPC). Inherited/germline mutations are associated with a hereditary predisposition to early PCa development and aggressive behavior. BRCA2, ATM and CHECK2 are the most frequently HRD-mutated genes. BRCA2-mutated tumors have unfavorable clinical and pathological characteristics, such as intraductal carcinoma. PARP inhibitors, due to the induction of synthetic lethality, have been therapeutically approved for mCRPC with HRD alterations. Mutations are detected in metastatic tissue, while a liquid biopsy is utilized during follow-up, recognizing acquired resistance mechanisms. The mismatch repair (MMR) pathway is another DNA repair mechanism implicated in carcinogenesis, although only 5% of metastatic PCa is affected. It is associated with aggressive disease. PD-1 inhibitors have been used in MMR-deficient tumors; thus, the MMR status should be tested in all metastatic PCa cases. A surrogate marker of defective DNA repair mechanisms is the tumor mutational burden. PDL-1 expression and intratumoral lymphocytes have ambivalent predictive value. Few experimental molecules have been so far proposed as potential biomarkers. Future research may further elucidate the role of DNA damage pathways in PCa, revealing new therapeutic targets and predictive biomarkers.

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Section: Future Therapeutic Perspectives and Emerging Biomarkersmentioning

confidence: 99%

DNA Damage Repair Pathways in Prostate Cancer: A Narrative Review of Molecular Mechanisms, Emerging Biomarkers and Therapeutic Targets in Precision Oncology

Grypari

Tzelepi

Gyftopoulos

2023

IJMS

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Silmitasertib in Combination With Cabozantinib Impairs Liver Cancer Cell Cycle Progression, Induces Apoptosis, and Delays Tumor Growth in a Preclinical Model

Haga,

Ray,

Ray

2024

Molecular Carcinogenesis

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The rising incidence of hepatocellular carcinoma (HCC) is a global problem. Several approved treatments, including immune therapy and multi‐tyrosine kinase inhibitors, are used for treatment, although the results are not optimum. There is an unmet need to develop highly effective chemotherapies for HCC. Targeting multiple pathways to attack cancer cells is beneficial. Cabozantinib is an orally available bioactive multikinase inhibitor and has a modest effect on HCC treatment. Silmitasertib is an orally bioavailable, potent CK2 inhibitor with a direct role in DNA damage repair and is in clinical trials for other cancers. In this study, we planned to repurpose these existing drugs on HCC treatment. We observed a stronger antiproliferative effect of these two combined drugs on HCC cells generated from different etiologies as compared to the single treatment. Global RNA‐seq analyses revealed a decrease in the expression of G2/M cell cycle transition genes in HCC cells following combination treatment, suggesting G2 phase cell arrest. We observed G2/M cell cycle phase arrest in HCC cells upon combination treatment compared to the single‐treated or vehicle‐treated control cells. The downregulation of CCNA2 and CDC25C following combination therapy further supported the observation. Subsequent analyses demonstrated that combination treatment inhibited 70 kDa ribosomal protein S6 kinase (p70S6K) phosphorylation, and increased Bim expression. Apoptosis of HCC cells were accompanied by increased poly (ADP‐ribose) polymerase cleavage and caspase‐9 activation. Next, we observed that a combination therapy significantly delayed the progression of HCC xenograft growth as compared to vehicle control. Together, our results suggested combining cabozantinib and silmitasertib would be a promising treatment option for HCC.

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Phase I Trial of the Multi-kinase Inhibitor Cabozantinib, a CYP3A4 Substrate, plus CYP3A4-Interacting Antiretroviral Therapy in People Living with HIV and Cancer (AMC-087)

Haigentz

Lee

Chiao

et al. 2023

Clinical Cancer Research

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Purpose: To evaluate the safety, pharmacokinetics, and pharmacodynamic effects of cabozantinib, a CYP3A4 substrate, in people living with HIV (PLWH) and cancer receiving antiretrovirals (ARVs). Experimental Design: Patients received a reduced dose of cabozantinib (20 mg PO daily) with strong CYP3A4 inhibitors (ARV ritonavir or non-ARV cobicistat, stratum A), or a standard 60 mg dose with ARVs that are CYP3A4 inducers (efavirenz or etravirine, stratum B) or non-interacting ARVs (stratum C). Initial dose escalation in stratum A and stratum B was performed based on tolerability. Results: 36 patients received cabozantinib plus ARVs, including 20 in stratum A, 9 in B, and 7 in C. The recommended initial cabozantinib dose for stratum A, B, and C were 20, 60, and 60 mg, respectively. Doses of 40 or 60 mg plus CYP3A4 inhibitors in stratum A and 100 mg plus CYP3A4 inducers in stratum B were associated with excessive toxicity, whereas 60 mg with non-interacting ARVs was not. The steady state minimal concentrations were lower at 20 mg in stratum A or 60 mg in stratum B compared to 60 mg in stratum C, while total exposure was only lower in 60 mg in stratum B compared to 60 mg in stratum C. Activity was observed in Kaposi sarcoma and an AXL-amplified sarcoma. Conclusions: Cabozantinib as a single agent should be initiated at 20 mg daily and 60 mg daily when taken concurrently with ARVs that are strong CYP3A4 inhibitors and inducers, respectively, with consideration for subsequent escalation per current cabozantinib guidelines.

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Cabozantinib combination therapy for the treatment of solid tumors: a systematic review

Cited by 4 publications

References 81 publications

DNA Damage Repair Pathways in Prostate Cancer: A Narrative Review of Molecular Mechanisms, Emerging Biomarkers and Therapeutic Targets in Precision Oncology

DNA Damage Repair Pathways in Prostate Cancer: A Narrative Review of Molecular Mechanisms, Emerging Biomarkers and Therapeutic Targets in Precision Oncology

Silmitasertib in Combination With Cabozantinib Impairs Liver Cancer Cell Cycle Progression, Induces Apoptosis, and Delays Tumor Growth in a Preclinical Model

Phase I Trial of the Multi-kinase Inhibitor Cabozantinib, a CYP3A4 Substrate, plus CYP3A4-Interacting Antiretroviral Therapy in People Living with HIV and Cancer (AMC-087)

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