Multi-tyrosine Kinase Inhibitor Research Articles

Anti-inflammatory effects of LCB 03-0110 on human corneal epithelial and murine T helper 17 cells.

Dry eye disease (DED) is a complicated disorder that impacts ocular surface and tear-film stability. Inflammation has recently been reported as the core mechanism and main therapeutic target of DED. Although anti-inflammatory drugs have been developed, they still have limited efficacy and various side effects. Recent reports have suggested that kinase inhibitors are beneficial for relieving inflammation. Therefore, this study aimed to investigate the anti-inflammatory effects of LCB 03-0110, a multi-tyrosine kinase inhibitor, on representative cell-based models (HCE- 2 and Th17 cells) of DED. While tacrolimus and tofacitinib, two different anti-inflammatory drugs that have entered clinical trials for DED treatment, did not induce any anti-inflammatory responses in HCE-2 cells, LCB 03-0110 significantly suppressed the phosphorylation of P38 and ERK and reduced the expression levels of IL-6 and IL-8 in HCE-2 cells treated with either LPS or poly(I:C). Moreover, LCB 03-0110 notably decreased the expression level of IL-17A in Th17 cells in a dose-dependent manner, whereas tofacitinib promoted IL-17A production at low concentrations but inhibited its expression at concentrations greater than 1 μM. In addition, LCB 03-0110 was found to be non-toxic to both HCE-2 and Th17 cells. In conclusion, these results suggest that LCB 03-0110 would be a promising drug candidate for the treatment of DED because of its advantages over tacrolimus and tofacitinib.

Phase II trial of multi-tyrosine kinase inhibitor ESK981 in combination with PD-1 inhibitor nivolumab in patients with metastatic castration-resistant prostate cancer.

Increasing the response rates of immune checkpoint inhibitors in patients with metastatic castration-resistant prostate cancer (mCRPC) presents a significant challenge. ESK981 is a multi-tyrosine kinase and PIKfyve lipid kinase inhibitor that augments immunotherapeutic responses. In this phase II study, ESK981 was combined with the PD-1 blocking monoclonal antibody nivolumab to test for potentially improved response rates in patients with mCRPC who have progressed on androgen receptor (AR)-targeted agents and chemotherapy. Eligible patients received ESK981 orally once daily for five consecutive days, followed by a two-day break. Patients were also treated with nivolumab intravenously on Day 1 of each 28-day cycle. The primary endpoints were a 50% reduction in prostate-specific antigen (PSA50), and safety. Secondary endpoints included radiographic progression free survival (rPFS) and overall survival (OS). Additional investigations included whole exome sequencing in patients. Ten patients were enrolled. The maximum PSA decline from baseline of 14% was achieved in only one patient. Grade 3 treatment-related adverse events (AEs) included fatigue, anemia, and lymphopenia. There were no Grade 4 events. The median rPFS was 3.7 months (95% CI, 1.6-8.4). The median OS was 9.6 months (95% CI, 1.8-22.4). The study was terminated due to futility after 10 patients. Whole exome sequencing identified AR amplification in 63% of patients (5/8). ESK981 + nivolumab showed no antitumor activity in patients with AR-positive (AR+) mCRPC. Further evaluation of ESK981 combined with the PD-1 inhibitor nivolumab in AR + mCRPC patients is not warranted. (Trial registration: ClinicalTrials.gov NCT04159896. Registration date: November 12, 2019.).

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

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.

Neoadjuvant Treatment With Regorafenib and Capecitabine Combined With Radiotherapy in Locally Advanced Rectal Cancer: A Multicenter Phase Ib Trial (RECAP)–SAKK 41/16

BackgroundThe multi tyrosine kinase inhibitor regorafenib is active in metastatic colorectal cancer. Improvement in clinical outcome by adding regorafenib to long-course chemoradiotherapy (LcCRT) was investigated in molecularly undefined LARC. MethodsPatients with T3-4 and/or N+ but M0 rectal cancer were included. Neoadjuvant LcRCT consisted in capecitabine (C) 825mg/m2 d1-d38 and 28 fractions of 1.8Gy (50.4Gy). Regorafenib was added d1-14 and d22-35 in 3 dose escalation (DE) cohorts (40mg/80mg/120mg). The recommended dose (RD) was used for the expansion (EXP) cohort. Primary endpoints were dose-limiting toxicity (DLT) for DE and pathological response (near-complete regression [npCR] or complete regression [pCR]) for EXP. ResultsOverall, 25 patients were included. Two DLTs occurred at the regorafenib dose level of 120 mg, thereby establishing the RD at 80mg daily. Among the 19 patients who were treated at the RD, 8 (42.1%; 1-sided 80% confidence interval [CI] (lower bound): 30.7%; 95% CI, 20.3%-66.5%) reached the primary endpoint (5 [26.3%] had npCR and 3 [15.8%] pCR). One additional patient received no surgery due to clinical complete response. All patients had R0 resections and clear circumferential margins. Postoperative complications occurred in 6 patients (35.3%). The most common grade ≥ 3 treatment-related adverse event in the EXP cohort was diarrhea (2 patients). ConclusionAdding regorafenib 80 mg to LcCRT in LARC resulted in both primary endpoints being met and yielded an expectedpathological response rate. Toxicity was manageable, and postoperative complications were as expected.

Management of follicular thyroid carcinoma.

Follicular thyroid carcinoma (FTC) is the second most common histological type of thyroid carcinoma. This review aims to summarize the available evidence and guidelines and provide an updated consensus regarding the management of FTC. The cytoarchitectural features of FTC are similar to those of follicular adenoma (FA), and it is difficult to preoperatively distinguish between FA and FTC. For nodules with Bethesda class III-V cytology, molecular test results (if available) should be considered before the operation. However, it should be noted that molecular tests are not available in all countries. The goals of initial surgical therapy for patients with FTC are to improve overall and disease-specific survival, reduce the risk of persistent/recurrent disease and associated morbidity, and permit accurate disease staging and risk stratification while minimizing treatment-related morbidity and unnecessary therapy. Previous studies have reported some prognostic factors such as distant metastasis, age, tumor size, vascular invasion, TERT promoter mutation, and histological subtype. In particular, the degree of vascular invasion is becoming increasingly important. Evaluating these prognostic factors is essential for prognostic prediction and precise management of patients with FTC. Recurrence and distant metastasis of FTC are treated with radioactive iodine (RAI). However, some FTCs become refractory to RAI. Multi-tyrosine kinase inhibitors such as sorafenib and lenvatinib are utilized for treating RAI-refractory FTCs. In addition, given that renin-angiotensin system (RAS) is the most common driver gene for FTC, it is also important to develop RAS inhibitors.

The tyrosine kinase inhibitor Nintedanib induces lysosomal dysfunctionality: Role of protonation-dependent crystallization processes

Nintedanib (NIN), a multi-tyrosine kinase inhibitor clinically approved for idiopathic pulmonary fibrosis and lung cancer, is characterized by protonation-dependent lysosomotropic behavior and appearance of lysosome-specific fluorescence emission properties. Here we investigate whether spontaneous formation of a so far unknown NIN matter within the acidic cell compartment is underlying these unexpected emissive properties and investigate the consequences on lysosome functionality. Lysosomes of cells treated with NIN, but not non-protonatable NIN derivatives, exhibited lysosome-associated birefringence signals co-localizing with the NIN-derived fluorescence emission. Sensitivity of both parameters towards vATPase inhibitors confirmed pH-dependent, spontaneous adoption of novel crystalline NIN structures in lysosomes. Accordingly, NIN crystallization from buffer solutions resulted in formation of multiple crystal polymorphs with pH-dependent fluorescence properties. Cell-free crystals grown at lysosomal-like pH conditions resembled NIN-treated cell lysosomes concerning fluorescence pattern, photobleaching dynamics, and Raman spectra. However, differences in birefringence intensity and FAIM-determined anisotropy, as well as predominant association with (intra)lysosomal membrane structures, suggested formation of a semi-solid NIN crystalline matter in acidic lysosomes. Despite comparable target kinase inhibition, NIN, but not its non-protonatable derivatives, impaired lysosomal functionality, mediated massive cell vacuolization, enhanced autophagy, deregulated lipid metabolism, and induced atypical phospholipidosis. Moreover, NIN exerted distinct phototoxicity, strictly dependent on lysosomal microcrystallization events. The spontaneous formation of NIN crystalline structures was also observable in the gut mucosa of orally NIN-treated mice. Summarizing, the here-described kinase inhibition-independent impact of NIN on lysosomal functionality mediates several of its cell biological activities and might contribute to NIN adverse effects.

Impact of genomic biomarkers on treatment decisions and clinical outcomes in patients with radioiodine-refractory thyroid cancer and treatment with multi-tyrosine kinase inhibitors - a multi-center registry analysis

Impact of genomic biomarkers on treatment decisions and clinical outcomes in patients with radioiodine-refractory thyroid cancer and treatment with multi-tyrosine kinase inhibitors - a multi-center registry analysis

Empagliflozin mitigates ponatinib-induced cardiotoxicity by restoring the connexin 43-autophagy pathway

BackgroundEmpagliflozin (EMPA), a selective sodium-glucose cotransporter type 2 (SGLT2) inhibitor, has been shown to reduce major adverse cardiovascular events in patients with heart failure of different etiologies, although the underlying mechanism still remains unclear. Ponatinib (PON) is a multi-tyrosine kinase inhibitor successfully used against myeloid leukemia and other human malignancies, but its cardiotoxicity remains worrisome. Cardiac connexins (Cxs) are both substrates and regulators of autophagy and responsible for proper heart function. Alteration in connexin expression and localization have been described in patients with heart failure. AimsTo assess whether EMPA can mitigate PON-induced cardiac dysfunction by restoring the connexin 43-autophagy pathway. Methods and ResultsMale C57BL/6 mice, randomized into four treatment groups (CNTRL, PON, EMPA, PON+EMPA) for 28 days, showed increased autophagy, decreased Cx43 expression as well as Cx43 lateralization, and attenuated systo-diastolic cardiac dysfunction after treatment with EMPA and PON compared with PON alone. Compared with CNTRL (DMSO), cardiomyocyte-differentiated H9c2 (dH9c2) cells treated with PON showed significantly reduced cell viability to approximately 20 %, decreased autophagy, increased cell senescence and reduced DNA binding activity of serum response factor (SRF) to serum response elements (SRE), which were paralleled by reduction in cardiac actin expression. Moreover, PON induced a significant increase of Cx43 protein and its S368-phosphorylated form (pS368-Cx43), as well as their displacement from the plasma membrane to the perinuclear and nuclear cellular region. All these effects were reverted by EMPA. ConclusionEMPA attenuates PON-induced cardiotoxicity by reducing senescence, enhancing the SRE-SRF binding and restoring the connexin 43-autophagy pathway. This effect may pave the way to use of SGLT2 inhibitors in attenuating tyrosine-kinase inhibitor cardiotoxicity.

Determining M2 macrophages content for the anti-tumor effects of metal-organic framework-encapsulated pazopanib nanoparticles in breast cancer

Pazopanib (PAZ), an oral multi-tyrosine kinase inhibitor, demonstrates promising cytostatic activities against various human cancers. However, its clinical utility is limited by substantial side effects and therapeutic resistance. We developed a nanoplatform capable of delivering PAZ for enhanced anti-breast cancer therapy. Nanometer-sized PAZ@Fe-MOF, compared to free PAZ, demonstrated increased anti-tumor therapeutic activities in both syngeneic murine 4T1 and xenograft human MDA-MB-231 breast cancer models. High-throughput single-cell RNA sequencing (scRNAseq) revealed that PAZ@Fe-MOF significantly reduced pro-tumorigenic M2-like macrophage populations at tumor sites and suppressed M2-type signaling pathways, such as ATF6-TGFBR1-SMAD3, as well as chemokines including CCL17, CCL22, and CCL24. PAZ@Fe-MOF reprogramed the inhibitory immune microenvironment and curbed tumorigenicity by blocking the polarization of M2 phenotype macrophages. This platform offers a promising and new strategy for improving the cytotoxicity of PAZ against breast cancers. It provides a method to evaluate the immunological response of tumor cells to PAZ-mediated treatment.

Larotrectinib efficacy for liver metastases in papillary thyroid carcinoma patient harboring SQSTM1–NTRK1 fusion

BackgroundPooled data analysis from three phase I/II larotrectinib clinical trials revealed that larotrectinib demonstrated rapid and durable disease control and a favorable safety profile for patients with neurotrophic-tropomyosin receptor kinase (NTRK) fusion positive thyroid carcinoma. Herein, we report the case of a patient with papillary thyroid carcinoma (PTC) and liver metastases who demonstrated a durable response to treatment with larotrectinib.Case presentationA 50-year-old female with PTC was referred to our hospital for postoperative observation. Computed tomography (CT) scan was performed to screen for distant metastasis, since thyroglobulin concentration increased gradually, and revealed multiple distant metastases, including multiple liver metastases. Radioactive iodine was administered at a dose of 100 mCi. However, uptake was observed only in the thyroid bed, and distant metastases had no avidity. As liver metastases progressed, lenvatinib (24 mg/day) was initiated after confirmation of liver metastases by liver biopsy 9 years and 1 month after the initial referral to our hospital. Since the multiple metastases became refractory for lenvatinib, the OncoGuide™ NCC Oncopanel System was performed, and the SQSTM1–NTRK1 gene fusion was confirmed. Larotrectinib was subsequently administered at a dose of 200 mg/day. The CT before the initiation of larotrectinib showed multiple liver metastases with a maximum diameter of 48 mm. The first CT evaluation at 1 month after the initiation of larotrectinib treatment showed that the tumor volume was reduced by 28% in the RECIST 1.1 criteria. After 3 months of larotrectinib treatment, a 38% reduction in the tumor volume was achieved as the best clinical response. The only side effect was grade 1 myalgia. At 12 months after the initiation of larotrectinib treatment, none of the lesions had progressed.ConclusionsIn conclusion, larotrectinib demonstrated effective antitumor activity against liver metastases of PTC, a relatively rare site of distant metastasis. Furthermore, the efficacy of larotrectinib was maintained, even though the patient had a history of multi-tyrosine kinase inhibitor treatment and a relatively infrequent fusion gene, SQSTM1–NTRK1.

Regorafenib plus FOLFIRINOX as first-line treatment for patients with RAS-mutant metastatic colorectal cancer (FOLFIRINOX-R trial): a dose-escalation study.

The combination of bevacizumab and FOLFIRINOX is used in patients with RAS-mutant metastatic colorectal cancer (RASm-mCRC). Regorafenib, an oral multi-tyrosine kinase inhibitor, has antiangiogenic properties, cytostatic effects and also true cytotoxic effects, unlike bevacizumab. The aim of this study was to determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) of the regorafenib-FOLFIRINOX combination in patients with RASm-mCRC. The FOLFIRINOX-R trial was a phase 1/2 study where the dose-escalation part (3 + 3 design with three dose levels, DLs) was completed before its early termination. FOLFIRINOX (14-day cycle) included oxaliplatin (standard dose), folinic acid, fluorouracil and irinotecan (150 or 180mg/m²). Regorafenib (120 or 160mg daily) was given from day 4 to day 10 of each cycle. Dose-limiting toxicity (DLT) was studied in the first three cycles. Eligibility criteria included ECOG performance status ≤ 1 and not previously treated RASm-mCRC. Thirteen patients (median age: 65 years; min-max: 40-76) were enrolled. DLT could not be evaluated in one patient (DL3) due to poor observance. The median treatment duration and median follow-up were 6.2 (min-max: 2.3-10) and 13.4 (min-max: 3.8-18.0) months, respectively. Dose was modified in 12/13 (92%) patients. One grade 3 hypokalemia occurred at DL2. MTD was not reached at DL3. Grade 3 diarrhea was recorded in 7/13 patients (13 events) equally distributed in all DLs. The RP2D for this regorafenib-FFX combination could not be determined due to a high prevalence of grade 3 diarrhea related to treatment as advised by our Independent Data Monitoring Committee. ClinicalTrials.gov : NCT03828799.

Thyroid carcinomas: the role of systemic therapies in internal medicine

The molecular pathogenesis of thyroid carcinoma is well studied and of importance for the treatment of advanced stages. Differentiated, poorly differentiated and anaplastic carcinomas originate in the follicular cells, while medullary carcinomas derive from the C‑cells. The prognosis of differentiated thyroid carcinoma is generally very favourable after surgery and radioiodine therapy. Where tumours progress and lose the ability to enrich iodine, curative treatment is usually not possible. Astrategy of watchful waiting is often appropriate. Activating mutations in BRAF or gene fusions of RET and NTRK provide opportunities for targeted therapies. These may be applied with the aim of restoring iodine uptake (redifferentiation). In the absence of molecular therapy targets, multityrosine kinase inhibitors (MKI) are the therapy of choice. If anaplastic thyroid carcinoma is suspected, rapid diagnostic workup including molecular pathology is warranted. Surgery where possible and radiochemotherapy are essential components of therapy. In the presence of aBRAF mutation, inhibition of BRAF and MEK is effective, even if it is not approved in Germany. Where molecular targets are lacking, combination therapy with the MKI lenvatinib and immune checkpoint inhibition is highly effective. Mutations in RET are present in the vast majority of cases of medullary thyroid carcinoma. In aggressive advanced disease, selective RET inhibition has recently been approved as first-line therapy and often leads to an objective response and long-lasting disease stabilisation. In summary, thyroid carcinomas are among the tumour entities for which molecularly targeted therapies can be used most frequently. The involvement of specialised centres is advisable.

HGG-30. TARGETED THERAPY OF PEDIATRIC HIGH GRADE GLIOMAS

Abstract BACKGROUND The prognosis for patients with pediatric high-grade glioma (pHGG) is poor despite aggressive multimodal therapy. Recent advances in understanding tumor biology facilitate utilization of targeted therapies (TT) in pediatric neuro-oncology. METHODS We analyzed the efficacy of targeted therapy in patients with progressive pHGG treated with TT according to molecularly-identified actionable events. Molecular characterization of the tumor included DNA panel and transcriptomic RNA sequencing. RESULTS Eighteen patients were included (median age 3.7 years, range 0.1-17.7) with anaplastic pleomorphic xanthoastrocytoma (n=10), infant-type hemispheric glioma (n=4), and diffuse high-grade glioma (n=4). Metastatic disease was present in 3/18 patients. Molecular genetic alterations included BRAF V600E mutations (n=8), NTRK1/2/3 fusions (n=4), ROS1 fusions (n=4), MET fusion (n=1), KIT P627L mutation (n=1). Eight patients received an NTRK/ALK/ROS1 inhibitor (entrectinib), seven patients received combination therapy with BRAF and MEK inhibitors (dabrafenib and trametinib), and one patient anti-BRAF monotherapy (dabrafenib). Two patients were treated with a multi-tyrosine kinase inhibitor (cabozantinib). The median duration of targeted therapy was 10.6 months (1-42). Most patients tolerated treatment well with no grade 4-5 toxicities. The overall response rate was 66% (12/18), including 4 complete (22%) and 8 partial responses (44%). At 12 months, PFS was 86% with dabrafenib/trametinib and 42% with entrectinib; at 18 months PFS was 44 % with dabrafenib plus trametinib and 42% with entrectinib. Three out of four patients with ROS1 rearranged glioma experienced disease progression on entrectinib after an initial good response in all cases; two of them subsequently received lorlatinib with clinical benefit. All four patients with NTRK1/2/3 rearranged gliomas remain on entrectinib therapy without signs of progression. Cabozantinib therapy resulted in prolonged complete and partial responses in both cases. CONCLUSIONS TT for patients with progressive pHGG is feasible and provides unexpectedly good clinical efficacy.

Efficacy of Pazopanib on Primary Patient-derived Undifferentiated Malignant Round Cell Sarcoma Line

Abstract Introduction: Undifferentiated round cell tumours (URCTs) are rare and less researched Ewing-like mesenchymal tumours that primarily affect bones and soft tissues. Therapeutic options for advanced URCT are limited. Pazopanib, a multi-tyrosine kinase and angiogenesis inhibitor, is currently used for managing advanced soft-tissue sarcoma. However, its efficacy in the treatment of URCT remains uncertain and has not been established. In this study, we have cultured and characterised a patient-derived URCT cell line to understand the in vitro growth properties and anti-cancer agent sensitivity. Materials and Methods: Primary cell culture was performed by mechanical and enzymatic dissociation of URCT tissue specimens to derive a cell line. Morphology, growth properties and immunological features characterised the cells. Further, the in vitro sensitivity for clinically used anti-cancer drugs was evaluated. Results: The URCT cell line was established from a high-grade round-cell tumour patient. The cells had mesenchymal morphology and showed cyclin B3 (CCNB3) positivity, which was confirmed in the tissue from the patient. The cells exhibited an anchorage-independent growth property and aggregated to form spheroids in a non-adherent in vitro system. Anti-cancer agents vincristine, doxorubicin, etoposide and pazopanib inhibited URCT cell proliferation. Pazopanib exhibited cytotoxic action in URCT cells, leading to cell death. Conclusions: This is an early report of cultured URCT cells expressing CCNB3, studied in vitro. The patient-derived model suggests the efficacy of pazopanib in URCT cells. The characterised line will be helpful to advance sarcoma studies.

A phase II study of cabozantinib and pembrolizumab in advanced gastric/gastroesophageal adenocarcinomas resistant or refractory to immune checkpoint inhibitors.

Most patients with metastatic gastroesophageal adenocarcinoma (mGEA) progress on immune checkpoint inhibitors (ICIs). Novel approaches to overcome resistance to ICI in mGEA are needed. Cabozantinib is a multi-tyrosine kinase inhibitor thought to enhance the immunomodulatory effects of ICI. This study evaluated the combination of cabozantinib and pembrolizumab in ICI refractory or resistant mGEA. Investigator-initiated, single-arm, single institution, and phase II study in patients with mGEA. Patients had progressed on ICI and/or had PD-L1 CPS score ≤10%. Cabozantinib dose was 40 mg p.o. daily on days 1-21 of a 21-day cycle, with pembrolizumab 200 mg i.v. on day 1. The primary endpoint was progression-free survival at 6 months (PFS-6). Twenty-seven patients were enrolled. Median age 58 years (24-87), female (n = 14), ECOG 0/1 = 13/14, GC/GEJ = 16/11, and non-Hispanic White/Hispanic/Asian = 12/8/7. The primary endpoint was met. After a median follow-up of 31.4 months (range 3.3-42.5), PFS-6 was 22.2% (95% CI 9.0-39.0). The median PFS and OS are 2.3 months (95% CI 1.7-4.1) and 5.5 months (3.1-14.0), respectively. The most common mutations were TP53 (78.3%) and CDH1/PIK3CA/CTNNB1 (17.4% each). The most common grade (G) treatment-related adverse events (TRAE) were diarrhea (25.9%), fatigue (18.5%), hypertension, and muscle cramps (14.8% each). G3-4 TRAE were seen in n = 3 patients (hypertension, thromboembolic event, esophageal perforation; each n = 1). No G5 was observed. The addition of cabozantinib to pembrolizumab shows clinical benefit in ICI-resistant or refractory mGEA with a tolerable safety profile. (ClinicalTrials.gov Identifier: NCT04164979. IRB Approved: UCI 18-124, University of California Irvine IRB#20195426.).

Side effects of dermato-oncologic therapies

Immune checkpoint inhibitors (ICIs) such as PD(L)1 and CTLA4 antibodies as well as targeted therapies such as BRAF and MEK inhibitors have significantly improved the systemic treatment of skin cancer in adjuvant and advanced therapy settings. All these drugs differ in their spectrum of side effects. The aim of this article is to provide an overview of the spectrum of side effects of dermato-oncological therapies and their management, taking into account the current literature. The most important side effects of ICIs, the CCR4 inhibitor mogamulizumab, the ImmTAC tebentafusp, the BRAF and MEK inhibitors and the multityrosine kinase inhibitor imatinib are considered. Side effects can manifest themselves in all organ systems. Chronic side effects and long-term harm are possible, especially with ICIs, and require close therapy monitoring and patient education. Knowledge of the side effects and the temporal, sometimes delayed course of their occurrence are essential for diagnosis and prompt initiation of therapy.

Molecular Characterization and Therapeutic Opportunities in KRAS Wildtype Pancreatic Ductal Adenocarcinoma.

To investigate the molecular characteristics of and potential for precision medicine in KRAS wildtype pancreatic ductal adenocarcinoma (PDAC). We investigated 27 patients with KRASWT PDAC at our institution. Clinical data were obtained via chart review. Tumor specimens for each subject were interrogated for somatic single nucleotide variants, insertion and deletions, and copy number variants by DNA sequencing. Gene fusions were detected from RNA-seq. A patient-derived organoid (PDO) was developed from a patient with a MET translocation and expanded ex vivo to predict therapeutic sensitivity prior to enrollment in a phase 2 clinical trial. Transcriptomic analysis showed our cohort may be stratified by the relative gene expression of the KRAS signaling cascade. The PDO derived from our patient harboring a TFG-MET rearrangement was found to have in vitro sensitivity to the multi-tyrosine kinase inhibitor crizotinib. The patient was enrolled in the phase 2 SPARTA clinical trial and received monotherapy with vebrelitinib, a c-MET inhibitor, and achieved a partial and durable response. KRASWT PDAC is molecularly distinct from KRASMUT and enriched with potentially actionable genetic variants. In our study, transcriptomic profiling revealed that the KRAS signaling cascade may play a key role in KRASWT PDAC. Our report of a KRASWT PDAC patient with TFG-MET rearrangement who responded to a cMET inhibitor further supports the pursuit of precision oncology in this sub-population. Identification of targetable mutations, perhaps through approaches like RNA-seq, can help enable precision-driven approaches to select optimal treatment based on tumor characteristics.

Cabozantinib in patients with unresectable and progressive metastatic phaeochromocytoma or paraganglioma (the Natalie Trial): a single-arm, phase 2 trial

Metastatic phaeochromocytomas and paragangliomas (MPPGs) are orphan diseases. Up to 50% of MPPGs are associated with germline pathogenic variants of the SDHB gene. These tumours and many non-familial MPPGs exhibit a phenotype that is characterised by abnormal angiogenesis. We aimed to assess the activity and safety of cabozantinib, an antiangiogenic multi-tyrosine kinase inhibitor, in patients with MPPGs. The Natalie Trial is a single-arm, phase 2 clinical trial being conducted at The University of Texas MD Anderson Cancer Center (Houston, TX, USA). Patients aged 18 years or older with histologically confirmed, progressive, and unresectable MPPGs, with an Eastern Cooperative Oncology Group performance status of 0-2, were treated with oral cabozantinib 60 mg/day. The primary endpoint was the investigator-assessed overall response rate per the Response Evaluation Criteria in Solid Tumours version 1.1 criteria. All outcomes were assessed in all evaluable participants who received any amount of study treatment. The trial is registered with ClinicalTrials.gov (NCT02302833) and is active but not recruiting. From March 10, 2015, to May 11, 2021, 17 patients (13 male participants and four female participants) were enrolled. The median follow-up was 25 months (IQR 18-49). The overall response rate was 25·0% (95% CI 7·3-52·4; four of 16 patients). Seven grade 3 adverse events were reported in six patients, including single cases of hand-and-foot syndrome, hypertension, rectal fistula, QT prolongation, and asymptomatic hypomagnesaemia, and two cases of asymptomatic elevations of amylase and lipase. There were no grade 4 adverse events and no patient died on-study. Cabozantinib shows promising activity in patients with MPPGs. Team NAT Foundation, Margaret Cazalot, and Clarence P Cazalot.

Abstract LB005: Identification of novel targets for MYC-driven hepatocellular carcinoma via transomics

Abstract Hepatocellular carcinoma (HCC) is an aggressive tumor, and treatment options for patients with unresectable HCC are limited to targeted therapies and immunotherapy. The activation and dysregulation of MYC have been implicated in multiple cancers, including HCC, where approximately 30% of human HCC samples show MYC gene amplification. However, it is challenging to target MYC directly. Therefore, we applied a novel approach to circumvent targeting MYC directly by leveraging Pepper’s proprietary transomic analysis platform, COMPASS, to identify novel targets that are predicted to mimic the effect of turning MYC off. Specifically, COMPASS unlocks functional drivers of disease to identify novel drug targets. To study the role of MYC in tumor biology, we utilize an HCC cell line with tunable MYC expression. We generate genomic, transcriptomic, proteomic, and phosphoproteomic data from samples with MYC-on and MYC-off and compare via COMPASS to identify novel targets that mimic turning MYC off. The MYC-conditional HCC cell line (EC4) allows the regulation of MYC expression via the tetracycline regulatory (Tet-Off) system. Four omic datasets were collected from each sample: genomics (next-generation sequencing, NGS), transcriptomics (NGS), proteomics (mass spectrometry), and phosphoproteomics (mass spectrometry). We employed the COMPASS target prioritization algorithm to identify and rank novel targets that mimic turning MYC off. Targets were then filtered to select those with an available pharmacological tool compound (PTC). The PTCs were used to evaluate the targets in the Huh-7 xenograft model of HCC. All targets were kinases or related to kinase activity and pathways. All PTCs inhibited tumor growth from 18.1-78.3%. One multi-tyrosine kinase inhibitor resulted in maximum tumor growth inhibition, resulting in stasis of tumor growth and increased survival compared with control vehicle-treated mice. We have previously shown how the COMPASS transomics analysis approach can identify novel drug targets for drug resistant EGFRm NSCLC. The data presented here on MYC-driven HCC further validates this approach for novel target identification. Ongoing work will investigate novel targets using gene silencing, as PTCs were unavailable for many of these novel high-ranked targets identified in this study. Further validation studies are ongoing against other difficult-to-treat MYC-driven cancers to identify novel clinical targets and drug candidates to circumvent the MYC pathway. Citation Format: Simon P. Fricker, Christopher J. Nicholson, Samuel J. Roth, Arudhir Singh, Caitlin Brown, Jon Hu, Petronela Buiga, Vishnu P. Kanakaveti, Anja Deutzmann, Dean Felsher, Samantha D. Strasser. Identification of novel targets for MYC-driven hepatocellular carcinoma via transomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB005.

Anlotinib for Metastatic Progressed Pheochromocytoma and Paraganglioma: A Retrospective Study of Real-World Data.

Pheochromocytomas (PCC) and paragangliomas (PGL) (collectively PPGL) are a type of rare hypervascular neuroendocrine tumors that are very challenging to treat. This study aimed to determine the efficacy and safety of the multi-tyrosine kinase inhibitor anlotinib for the treatment of locally advanced or metastatic (LA/M) PPGL. A total of 37 eligible patients with unresectable or progressive LA/M PPGL were enrolled. Of them, 27 patients received anlotinib alone (n = 19) or in combination (n = 8) with radionuclide therapies, including peptide receptor radionuclide therapy (PRRT) and iodine 131 meta-iodobenzylguanidine (131I-MIBG). The primary endpoints included objective response rate (ORR), defined as partial response (PR) or complete response (CR), and disease-control rate, defined as PR, CR, or stable disease (SD). The secondary endpoints were progression-free survival (PFS), duration of response, and drug safety. In the efficacy evaluation for all 27 patients, the ORR was 44.44% (95% CI: 24.4%-64.5%) and disease-control rate was 96.29% (95% CI: 88.7%-100%). Twelve cases (44.44%) achieved PR, 14 (51.85%) SD. The median PFS was 25.2 months (95% CI: 17.2 months to not reached). PFS was shorter in the anlotinib monotherapy group than in the group receiving anlotinib in combination with radionuclide therapy (P = .2). There were no serious treatment-related AEs. Anlotinib monotherapy or in combination with radionuclide therapies shows promising efficacy and safety for the treatment of LA/M PCC and PGL. Multi-tyrosine kinase inhibitors might represent a novel therapeutic strategy for patients with PPGL; however, large-scale prospective randomized, blinded, controlled clinical research studies are required.