Use Of Multikinase Inhibitors Research Articles

Ten years' real-life experience on the use of multikinase inhibitors in patients with advanced differentiated thyroid cancer.

To evaluate objective response rates (ORR), progression-free survival (PFS), and overall survival (OS) associated with tyrosine kinase inhibitors (TKIs) in patients with radioiodine refractory differentiated thyroid cancer (RR-DTC). Additionally, to compare: (i) ORR and PFS among patients treated with lenvatinib and sorafenib; (ii) ORR and PFS among patients receiving lenvatinib as first-line vs. second-line and; (iii) adverse effects (AEs) observed in patients treated with these medications. Retrospective analysis of RR-DTC adult patients treated with TKIs at the Division of Endocrinology, Hospital de Clinicas, University of Buenos Aires (March 2011-November 2023). Among 43 patients included in the study, 32 received sorafenib (30 as first-line and 2 as second-line), while 29 received lenvatinib (12 as first-line and 17 as second-line). The median PFS and OS for the entire cohort were 32.7 and 39.0 months, respectively. Lenvatinib demonstrated a significantly higher ORR compared to sorafenib (37.9% vs. 9.4%, p = 0.008). However, both drugs exhibited similar median PFS (23.2 vs. 16.0 months, p = 0.419). No significant difference was observed in ORR and PFS between patients receiving first-line vs. second-line lenvatinib. Sorafenib-treated patients experienced higher rates of hand-foot skin syndrome (69% vs. 41%, p = 0.032) and alopecia (25% vs. 3%, p = 0.018), whereas lenvatinib-treated patients had higher rates of proteinuria (31% vs. 0%, p < 0.001) and grade 3 hypertension (31% vs. 9%, p = 0.034). TKIs demonstrated efficacy and tolerability comparable to real-world data in RR-DTC. PFS was not statistically different between sorafenib and lenvatinib. Our study will help guide physicians in making informed decisions regarding treatment sequencing with TKIs in these patients.

Perspective on the Role of Gut Microbiome in the Treatment of Hepatocellular Carcinoma with Immune Checkpoint Inhibitors.

Background and Objectives: Hepatocellular carcinoma (HCC) is the leading cause of liver cancer worldwide and has a high mortality rate. Its incidence has increased due to metabolic-associated liver disease (MAFLD) epidemics. Liver transplantation and surgery remain the most resolute measures. Despite the optimistic use of multi-kinase inhibitors, namely sorafenib, the co-existence of chronic liver disease made the response rate low in these patients. Immune checkpoint inhibitors (ICIs) have become a promising hope for certain advanced solid tumors and, also, for advanced HCC. Unfortunately, a large cohort of patients with HCC fail to respond to immunotherapy. Materials and Methods: We conducted a narrative search on the main medical databases for original articles, reviews, meta-analyses, randomized clinical trials, and case series using the following keywords and acronyms and their associations: hepatocellular carcinoma, immunotherapy, checkpoint inhibitors, gut microbiota, and fecal microbiota transplantation. Results: ICIs are a promising and sufficiently safe treatment option for HCC. In detail, they have significantly improved survival and prognosis in these patients vs. sorafenib. Although there are several highlighted mechanisms of resistance, the gut microbiota signature can be used both as a response biomarker and as an effect enhancer. Practically, probiotic dose-finding and fecal microbiota transplantation are the weapons that can be used to increase ICI's treatment-response-reducing resistance mechanisms. Conclusion: Immunotherapy has been a significant step-up in HCC treatment, and gut microbiota modulation is an effective liaison to increase its efficacy.

The Role of a Neoadjuvant RET Inhibitor in Medullary Thyroid Cancer

The Role of a Neoadjuvant <i>RET</i> Inhibitor in Medullary Thyroid Cancer

Potential use of multikinase inhibitors in immunosuppressed patients with malignancies including thyroid cancer

In this article, we focus on a variety of immunosuppression scenarios and whether multikinase inhibitors, as systemic therapy for advanced thyroid carcinoma (TC), could be useful for the treatment of immunocompromised patients with TC. Lenvatinib and sorafenib, among other MKIs, have become the standard of care for advanced TC based on their efficacy data and despite their adverse effects. Currently, published data on MKIs in immunosuppressed patients are scarce. Secondary malignancies can arise in immunosuppressed patients who have undergone solid organ transplantation, human immunodeficiency virus–infected patients, and hematopoietic stem cell transplant recipients. This review will explore different immunosuppression settings, the risk of secondary malignancies in immunosuppressed patients, and the special characteristics of this population. Some considerations regarding anticancer treatment in immunosuppressed patients with advanced malignancies are reviewed.

The importance of the RET gene in thyroid cancer and therapeutic implications.

Since the discovery of the RET receptor tyrosine kinase in 1985, alterations of this protein have been found in diverse thyroid cancer subtypes. RET gene rearrangements are observed in papillary thyroid carcinoma, which result in RET fusion products. By contrast, single amino acid substitutions and small insertions and/or deletions are typical of hereditary and sporadic medullary thyroid carcinoma. RET rearrangements and mutations of extracellular cysteines facilitate dimerization and kinase activation, whereas mutations in the RET kinase coding domain drive dimerization-independent kinase activation. Thus, RET kinase inhibition is an attractive therapeutic target in patients with RET alterations. This approach was initially achieved using multikinase inhibitors, which affect multiple deregulated pathways that include RET kinase. In clinical practice, use of multikinase inhibitors in patients with advanced thyroid cancer resulted in therapeutic efficacy, which was associated with frequent and sometimes severe adverse effects. However, remarkable progress has been achieved with the identification of novel potent and selective RET kinase inhibitors for the treatment of advanced thyroid cancer. Although expanded clinical validation in future trials is needed, the sustained antitumoural activity and the improved safety profile of these novel compounds is opening a new exciting era in precision oncology for RET-driven cancers.

1918P Final analysis of RIFTOS MKI, a global, non-interventional study assessing the use of multikinase inhibitors (MKIs) for the treatment of patients with asymptomatic radioactive iodine-refractory differentiated thyroid cancer (RAI-R DTC)

1918P Final analysis of RIFTOS MKI, a global, non-interventional study assessing the use of multikinase inhibitors (MKIs) for the treatment of patients with asymptomatic radioactive iodine-refractory differentiated thyroid cancer (RAI-R DTC)

Specificity of hand-foot skin reaction induced by multikinase inhibitors: clinical, histological and ultrasound characteristics

Background. Multikinase inhibitors of angiogenesis are currently the most effective group of drugs in target therapy for cancer. They are associated with a high prevalence of a specific cutaneous adverse reaction, which manifests as a hand-foot skin reaction (HFSR). This side effect is quite prominent in the majority of patients, usually graded as II–III degree, which leads to the dose reduction and even discontinuation of the drug. The study objective is to evaluate clinical, histological and ultrasound characteristics of a HFSR associated with MKI treatment, and to assess the influence of a HFSR on patient’s quality of life. Materials and methods. The study included 46 patients with HFSR, who were previously treated with sorafenib or lenvatinib. Clinical characteristics of HFSR, including severity grading, were evaluated. We also performed ultrasound and histological examinations and assess the Dermatology Life Quality Index. Results. Grade III HFSR was in 5 (10.86 %) patients, grade II – in 25 (54.35 %), and grade I – in 16 (34.79 %). Dermatology Life Quality Index depended on the HFSR severity, with the mean value 24.5 ± 2.4. Pathomorphological examination revealed irregular epidermal proliferation with hypertrophic psoriasiform acanthosis, minimal keratinocyte vacuolization, few apoptotic figures, dyskeratosis, hyperkeratosis and microvessel dilation in the papillary dermis. Ultrasound examination showed increased vascularization in papillary and reticular dermis in affected skin areas, which was more prominent in patients with severe degrees of HFSR. The pronounced enhancement of vascularization was detected in fragmented hypoechogenic sites along the border of papillary and reticular dermis and in similar sites along the border of dermis and hypodermis. Conclusion. The use of multikinase inhibitors leads to pronounced changes not only in the surface layers of the skin, but also in the dermis and subcutaneous fat, which significantly worsens the quality of life of patients. This indicates the need to search for pathogenetically based methods of treatment of HFSR and create practical guidelines for supportive treatment of patients with HFSR taking multikinase inhibitors.

Salvage Therapy With Multikinase Inhibitors and Immunotherapy in Advanced Adrenal Cortical Carcinoma.

BackgroundMedian overall survival is 12 to 15 months in patients with metastatic adrenal cortical carcinoma (ACC). Etoposide, doxorubicin, and cisplatin with or without the adrenolytic agent mitotane is considered the best first-line approach in this context, but has limited activity and no curative potential; additional salvage therapeutic options are needed.MethodsFifteen total patients with recurrent/metastatic ACC were treated with single-agent multikinase inhibitors (MKI) (n = 8), single-agent PD-1 inhibition (n = 8), or cytotoxic chemotherapy plus PD-1 inhibition (n = 4) at our institution as later-line systemic therapies in efforts to palliate disease and attempt to achieve a therapeutic response when not otherwise possible using standard approaches.ResultsTwo of 8 patients (25%) treated with single-agent MKI achieved a partial response (PR), including 1 PR lasting 23.5 months. Another 3 patients (38%) had stable disease (SD); median progression-free survival (PFS) with single-agent MKI was 6.4 months (95% confidence interval [CI] 0.8—not reached). On the other hand, 2 of 12 patients (17%) treated with PD-1 inhibitors (either alone or in combination with cytotoxic chemotherapy) attained SD or better, with 1 patient (8%) achieving a PR; median PFS was 1.4 months (95% CI 0.6-2.7).ConclusionsOur single-institution experience suggests that select ACC patients respond to late-line MKI or checkpoint inhibition despite resistance to cytotoxic agents. These treatments may be attractive to ACC patients with limited other therapeutic options. The use of MKI and immunotherapy in ACC warrants prospective investigation emphasizing parallel correlative studies to identify biomarkers that predict for response.

DDR1 regulates thyroid cancer cell differentiation via IGF-2/IR-A autocrine signaling loop.

Patients with thyroid cancers refractory to radioiodine (RAI) treatment show a limited response to various therapeutic options and a low survival rate. The recent use of multikinase inhibitors has also met limited success. An alternative approach relies on drugs that induce cell differentiation, as the ensuing increased expression of the cotransporter for sodium and iodine (NIS) may partially restore sensitivity to radioiodine. The inhibition of the ERK1/2 pathway has shown some efficacy in this context. Aggressive thyroid tumors overexpress the isoform-A of the insulin receptor (IR-A) and its ligand IGF-2; this IGF-2/IR-A loop is associated with de-differentiation and stem-like phenotype, resembling RAI-refractory tumors. Importantly, IR-A has been shown to be positively modulated by the non-integrin collagen receptor DDR1 in human breast cancer. Using undifferentiated human thyroid cancer cells, we now evaluated the effects of DDR1 on IGF-2/IR-A loop and on markers of cell differentiation and stemness. DDR1 silencing or downregulation caused significant reduction of IR-A and IGF-2 expression, and concomitant increased levels of differentiation markers (NIS, Tg, TSH, TPO). Conversely, markers of epithelial-to-mesenchymal transition (Vimentin, Snail-2, Zeb1, Zeb2 and N-Cadherin) and stemness (OCT-4, SOX-2, ABCG2 and Nanog) decreased. These effects were collagen independent. In contrast, overexpression of either DDR1 or its kinase-inactive variant K618A DDR1-induced changes suggestive of less differentiated and stem-like phenotype. Collagen stimulation was uneffective. In conclusion, in poorly differentiated thyroid cancer, DDR1 silencing or downregulation blocks the IGF-2/IR-A autocrine loop and induces cellular differentiation. These results may open novel therapeutic approaches for thyroid cancer.

Clinically relevant drug interactions with multikinase inhibitors: a review.

Multikinase inhibitors (MKIs), including the tyrosine kinase inhibitors (TKIs), have rapidly become an established factor in daily (hemato)-oncology practice. Although the oral route of administration offers improved flexibility and convenience for the patient, challenges arise in the use of MKIs. As MKIs are prescribed extensively, patients are at increased risk for (severe) drug–drug interactions (DDIs). As a result of these DDIs, plasma pharmacokinetics of MKIs may vary significantly, thereby leading to high interpatient variability and subsequent risk for increased toxicity or a diminished therapeutic outcome. Most clinically relevant DDIs with MKIs concern altered absorption and metabolism. The absorption of MKIs may be decreased by concomitant use of gastric acid-suppressive agents (e.g. proton pump inhibitors) as many kinase inhibitors show pH-dependent solubility. In addition, DDIs concerning drug (uptake and efflux) transporters may be of significant clinical relevance during MKI therapy. Furthermore, since many MKIs are substrates for cytochrome P450 isoenzymes (CYPs), induction or inhibition with strong CYP inhibitors or inducers may lead to significant alterations in MKI exposure. In conclusion, DDIs are of major concern during MKI therapy and need to be monitored closely in clinical practice. Based on the current knowledge and available literature, practical recommendations for management of these DDIs in clinical practice are presented in this review.

Second interim analysis of RIFTOS MKI, a global non-interventional study assessing the use of multikinase inhibitors (MKIs) in the treatment of patients with asymptomatic radioactive iodine-refractory differentiated thyroid cancer (RAI-R DTC).

6081Background: Sorafenib and lenvatinib are oral MKIs approved for the treatment of RAI-R DTC; however, there is no consensus on when patients with asymptomatic RAI-R DTC should start treatment wi...

Vascular endothelial growth factor (VEGF) antibody significantly increases the risk of hand-foot skin reaction to multikinase inhibitors (MKIs): A systematic literature review and meta-analysis.

SummaryWith the use of multikinase inhibitors (MKIs) having emerged in recent years, skin toxicities such as hand–foot skin reaction (HFSR) are primary side effects, and they lack effective prediction methods. Here, we updated a previous systematic review by establishing a meta‐analysis of the risk of developing HFSR among patients receiving MKIs and antivascular endothelial growth factor antibody. Publications from PubMed and abstracts presented at the American Society of Clinical Oncology Annual Meeting up to February 5, 2015, were searched to identify relevant studies, and a total of 236 patients with metastatic tumours in nine trials were included for analysis. In the meta‐analysis, the pooled incidence rates of all‐grade and high‐grade HFSR among patients who received the combination therapy were 56.9% [95% confidence interval (CI), 45%‐71.1%] and 14.3% (95% CI, 9%‐24.2%), respectively, with significant differences observed with MKI monotherapy (P < .05). Further subgroup analysis demonstrated that increasing the dosages of bevacizumab (77.8% vs 51.1%, P = .04) and MKIs (64.3% vs 52.6%, P = .02) significantly increased HFSR incidence. Moreover, combination with chemotherapy exerted a minimal effect on HFSR risk (61% vs 55.3%, P = .5). This updated review and meta‐analysis confirm the increased risk of HFSR incidence due to the use of MKIs and antivascular endothelial growth factor antibody. Thus, using these therapies requires safety standards.

465P - Interim baseline characteristics from RIFTOS MKI, a global non-interventional study assessing the use of multikinase inhibitors (MKIs) in the treatment of patients with asymptomatic radioactive iodine-refractory differentiated thyroid cancer (RAI-R DTC): A European subgroup analysis

465P - Interim baseline characteristics from RIFTOS MKI, a global non-interventional study assessing the use of multikinase inhibitors (MKIs) in the treatment of patients with asymptomatic radioactive iodine-refractory differentiated thyroid cancer (RAI-R DTC): A European subgroup analysis

Interim baseline characteristics from RIFTOS MKI, a global non-interventional study assessing the use of multikinase inhibitors (MKIs) in the treatment of patients with asymptomatic radioactive iodine-refractory differentiated thyroid cancer (RAI-R DTC).

6084 Background: RIFTOS MKI was designed to compare the time to symptomatic progression from study entry in patients with RAI-R DTC for whom there was a decision to treat or not to treat with an MKI in the real-life setting. Here, we report interim baseline characteristics for the first 274 patients enrolled in the study. Methods: RIFTOS MKI is a non-interventional study enrolling patients with asymptomatic RAI-R DTC. The decision to initiate MKIs at study entry was at the discretion of the treating physician. Final analysis will be performed once 700 patients have been enrolled and the last enrolled patient has been followed for 24 months. Results: Of 274 patients, the median duration of observation was 169.5 days. Patients have been enrolled from USA (n = 74), Japan (n = 55), Europe (n = 80), and rest of the world (n = 65); 54% were female and the median age was 68 years. Most patients had an ECOG performance status of 0 or 1 (97%) and distant metastases (81%). The most frequent histology was papillary (73%). The median time from initial diagnosis of DTC to study entry was 7 years. RAI refractoriness was mainly due to lack of RAI uptake (60%), primarily in Japan (80%). Japan also had the shortest median time from RAI classification to initial visit (2 months) vs other regions, and the average dose per RAI treatment and median cumulative activity of RAI were lower in Japanese patients (3.4 and 3.7 GBq, respectively) (Table). Conclusions: The RIFTOS MKI study is the largest non-interventional study in RAI-R DTC. The regional differences in treatment history observed in the RIFTOS MKI study reflect differences in accessibility and treatment practice. The study is ongoing. Clinical trial information: NCT02303444. [Table: see text]

Palmarplantar erythrodysesthesia in the patients with oncological pathology treated with multikinase inhibitors and the method for its correction

Introduction. The modern anti-tumour preparations from the group of multikinase inhibitors exhibit the high clinical effectiveness. Courses of therapy with such medications are indispensable and vitally important for the treatment of the patients presenting with oncological pathology but, unfortunately, happen to give rise to the development of a toxic reaction in the form of рalmar-plantar erythrodysesthesia which not infrequently prevents the completion of the full-scale treatment. The determination of the adequate skin condition is an indispensable component of the combined treatment of the oncological patients. Materials and methods. The present study included 9 patients treated with various preparations from the group of multikinase inhibitors. All of them developed toxic cutaneous reactions in the form of grade II-III palmar-plantar erythrodysesthesia which was corrected with the use of thioctic acid-based preparation at a daily dose of 600 mg given during 14 days in the combination with pharmaphoresis of the cream containing 0.1% of betamethasone valerate. Results. The use of the proposed therapeutic modality resulted in the reduction of the severity of the clinical manifestations of palmar-plantar erythrodysesthesia, such as erythema, infiltration, desquamation, fissures, etc. Simultaneously, the treatment eliminated certain subjective symptoms including pruritus, pain, and paresthesia. Taken together, these effects significantly improved the patients’ condition and allowed the course of antitumour therapy to be totally completed. Conclusion. The patients presenting with palmar-plantar erythrodysesthesia should be managed with the use of multikinase inhibitors in the combination with the oral administration of a thioctic acid-based preparation and local pharmaphoresis of the cream containing 0.1% of betamethasone valerate.

Trends and Predictors of Chemotherapy Use among Thyroid Cancer Patients in the National Cancer Database (2004-2013)

Background/Aim: Beginning in 2011, the Food and Drug Administration (FDA) approved the use of multikinase inhibitors (MKIs) for medullary thyroid cancers (MTCs), and in 2013 MKIs were approved for metastatic differentiated thyroid cancers (DTCs). However, little is known about the use of chemotherapy in thyroid cancer patients. Thus, the goal of our study was to describe patterns of chemotherapy use, including MKIs, among DTC and MTC patients in the National Cancer Database (NCDB). Methods: Chemotherapy use, along with other treatment types (surgery and radiation), was assessed between 2004 and 2013. The primary predictor was the year of diagnosis (2004-2010 and 2011-2013), based on the FDA's approval of chemotherapy for MTC (2011). Baseline use of MKIs in DTCs in 2013 was also examined. Multivariable logistic regression was used to estimate odds ratios (OR) and 95% CI of receipt of chemotherapy. Results: Overall, 199,654 patients were included in our analytic sample with 194,667 nonmetastatic DTCs, 1,633 metastatic DTCs, and 3,354 MTCs. Among MTCs, chemotherapy use significantly increased from 3.1% in 2004-2010 to 5.0% in 2011-2013 (p = 0.018) in unadjusted and adjusted (OR = 1.54, 95% CI: 1.00, 2.36) analyses. In metastatic DTCs, 4.9% of patients received chemotherapy in 2013, which was not significantly higher than in previous years (p = 0.755). Conclusions: Overall, chemotherapy use among MTCs increased marginally following the FDA's approval of MKIs in 2011, although their use remains very low. MKIs were infrequently used in metastatic DTCs in 2013. Future studies examining patterns of chemotherapy in thyroid cancer patients are warranted.

Multikinase Inhibitors Induce Cutaneous Toxicity through OAT6-Mediated Uptake and MAP3K7-Driven Cell Death.

The use of multikinase inhibitors (MKI) in oncology, such as sorafenib, is associated with a cutaneous adverse event called hand-foot skin reaction (HFSR), in which sites of pressure or friction become inflamed and painful, thus significantly impacting quality of life. The pathogenesis of MKI-induced HFSR is unknown, and the only available treatment options involve dose reduction or discontinuation of therapy, which have negative effects on primary disease management. To investigate the underlying mechanisms by which sorafenib promotes keratinocyte cytotoxicity and subsequent HFSR induction, we performed a transporter-directed RNAi screen in human epidermal keratinocytes and identified SLC22A20 (OAT6) as an uptake carrier of sorafenib. Further investigations into the intracellular mechanism of sorafenib activity through in situ kinome profiling identified the mitogen-activated protein kinase MAP3K7 (TAK1) as a target of sorafenib that induces cell death. Finally, we demonstrate that sorafenib induced keratinocyte injury in vivo and that this effect could be reversed by cotreatment with the OAT6 inhibitor probenecid. Collectively, our findings reveal a novel pathway that regulates the entry of some MKIs into keratinocytes and explains the basis underlying sorafenib-induced skin toxicity, with important implications for the therapeutic management of HFSR.

The treatment landscape in thyroid cancer: a focus on cabozantinib.

Although patients with thyroid cancer generally fare well, there is a subset for which this is not necessarily true. Progress in understanding the molecular aberrations in thyroid cancer has led to a change in the management of these cases. Since 2011, four multikinase inhibitors (MKIs) have been approved by the US Food and Drug Administration for thyroid cancer – cabozantinib and vandetanib for medullary thyroid cancer and sorafenib and lenvatinib for differentiated thyroid cancer. This change in the treatment landscape has raised challenges for practitioners who may not be familiar with the use of MKIs or with the treatment and natural history of advanced thyroid cancer in general. This article reviews the epidemiology, molecular drivers, and initial treatment of patients with thyroid cancer and offers practical guidance to assist with the determination of when to appropriately start an MKI. As an example, cabozantinib and its efficacy are discussed in detail. Close monitoring is required for all patients on targeted agents to assess for adverse effects and response to therapy. An approach to managing drug-related adverse events is detailed. Since these drugs are not curative and have not yet proven to prolong overall survival, it is critical to weigh the risks and benefits of treatment at every visit. The potential value of changing to a different agent following failure of an MKI is also addressed.

Evaluation of in vivo responses of sorafenib therapy in a preclinical mouse model of PTEN-deficient of prostate cancer.

BackgroundDespite recent advances in the treatment for advanced prostate cancer, outcomes remain poor. This lack of efficacy has prompted the development of alternative treatment strategies. In the present study we investigate the effects of the multikinase inhibitor sorafenib in a genetically engineered mouse model of prostate cancer and explore the rational combination with the mTOR inhibitor everolimus.MethodsConditional prostate specific PTEN-deficient knockout mice were utilized to determine the pharmacodynamic and chemopreventive effects of sorafenib. This mouse model was also used to examine the therapeutic efficacy of sorafenib alone or in combination with everolimus. Preclinical efficacy was assessed by comparing the reduction of tumor burden, proliferation, angiogenesis and the induction of apoptosis. Molecular responses were assessed by immunohistochemical, TUNEL and western blot assays.ResultsPharmacodynamic analysis revealed that a single dose of sorafenib decreased activation of the PI3K/AKT/mTOR signaling axis at doses of 30–60 mg/kg, but activated JAK/STAT3 signaling. Levels of cleaved casapase-3 increased in a dose dependent manner. Chemoprevention studies showed that chronic sorafenib administration was capable of inhibiting tumor progression through the reduction of cancer cell proliferation, angiogenesis and the induction of apoptosis. In intervention models of established castration-naïve and castration-resistant prostate cancer, treatment with sorafenib provided modest but statistically insignificant reduction in tumor burden. However, sorafenib significantly inhibited cancer cell proliferation and MVD but had minimal effects on the induction of apoptosis. Interestingly, the administration of sorafenib increased the expression levels of the androgen receptor, p-GSK3β and p-ERK1/2 in castration-resistant prostate cancers. In both intervention models, combination therapy demonstrated a clear tendency of enhanced antitumor effects over monotherapy. Notably, the treatment combination of sorafenib and everolimus overcame therapeutic escape from single agent therapy in castration-resistant prostate cancers.ConclusionsIn summary, we provide insights into the molecular responses of sorafenib therapy in a clinically relevant model of prostate cancer and present preclinical evidence for the development of targeted treatment strategies based on the use of multikinase inhibitors in combination with mTOR inhibitors for the treatment of advanced prostate cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0509-x) contains supplementary material, which is available to authorized users.

Abstract 3795: Cabozantinib affects multiple signaling pathways in glioblastoma and is effective in a subset of xenograft tumors

Abstract Background: Glioblastoma (GBM) is the most common and aggressive form of brain tumor characterized by poor prognosis and high recurrence rate. Several new targeted agents are being considered for the adjuvant treatment of GBMs. Cabozantinib, a multi-kinase currently in clinical trials for several malignancies, including glioblastoma, targets c-Met and VEGFR2 receptors, as well as Ret, Kit, Flt-1/3/4, Tie2, and AXL. Our goal is to first evaluate sensitivity and molecular response of patient-derived GBM cancer stem cells (CSCs) to XL184 in vitro. Anti-tumor efficacy of cabozantinib as a single agent and in combination with the DNA-alkylating agent temozolomide (TMZ) in orthotopic xenografts was then evaluated. Methods: Neurospheres enriched in CSCs were cultured from resected GBM tumors. Sensitivity to cabozantinib was determined in vitro. Cells were treated (IC40) in triplicate, and cell lysates were analyzed by reverse phase protein microarrays. GBM CSCs were implanted intracranially into nude mice. Cabozantinib was administered by oral gavage at a dose of 60mg/kg for 4 weeks (5 days/week) as a single agent or in combination with 40mg/kg TMZ. Tumor growth and response to treatment were monitored by non-invasive in vivo biolumiescent imaging (BLI) using the Xenogen IVIS System (Caliper Life Sciences), and overall survival. Results: Sensitivity to cabozantinib treatment varied for the different GBM CSCs. From 70 proteins and phosphoproteins measured, 29 distributed among several signaling pathways were significantly altered after treatment in both resistant and sensitive GBM CSCs. Cabozantinib single agent treatment reduced GBM tumor growth and increased mouse survival in two xenograft lines. Cabozantinib monotherapy reduced tumor size, as measured by BLI, but had no significant effect on overall survival for another xenograft line, however, the combination treatment resulted in sensitization of these xenografts to TMZ treatment. Conclusion: The use of multi-kinase inhibitors is a promising strategy for GBMs, and given the range of responses, identifying predictive biomarkers, though challenging, will be invaluable for patient stratification. Citation Format: Ana C. deCarvalho, Kimberly Arnold, Claudius Mueller, Emanuel F. Petricoin, Laila M. Poisson, Tom Mikkelsen. Cabozantinib affects multiple signaling pathways in glioblastoma and is effective in a subset of xenograft tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3795. doi:10.1158/1538-7445.AM2014-3795