ly-2157299 and Neoplasm-Metastasis

We assessed the safety, efficacy, and pharmacokinetics of the transforming growth factor beta (TGFβ) receptor inhibitor galunisertib co-administered with the anti-programmed death-ligand 1 (PD-L1) antibody durvalumab in recurrent/refractory metastatic pancreatic cancer previously treated with ≤2 systemic regimens.. This was a two-part, single-arm, multinational, phase Ib study. In a dose-finding phase, escalating oral doses of galunisertib were co-administered on days 1-14 with fixed-dose intravenous durvalumab 1500 mg on day 1 every 4 weeks (Q4W), followed by an expansion cohort phase.. The galunisertib recommended phase II dose (RP2D) when co-administered with durvalumab 1500 mg Q4W was 150 mg two times per day. No dose-limiting toxicities were recorded. Among 32 patients treated with galunisertib RP2D, 1 patient had partial response, 7 had stable disease, 15 had objective progressive disease, and 9 were not evaluable. Disease control rate was 25.0%. Median overall survival and progression-free survival were 5.72 months (95% CI: 4.01 to 8.38) and 1.87 months (95% CI: 1.58 to 3.09), respectively. Pharmacokinetic profiles for combination therapy were comparable to those published for each drug. There was no association between potential biomarkers and treatment outcomes.. Galunisertib 150 mg two times per day co-administered with durvalumab 1500 mg Q4W was tolerable. Clinical activity was limited. Studying this combination in patients in an earlier line of treatment or selected for predictive biomarkers of TGFβ inhibition might be a more suitable approach.. ClinicalTrials.gov identifier: NCT02734160.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; Disease Progression; Europe; Female; Humans; Immune Checkpoint Inhibitors; Male; Middle Aged; Neoplasm Metastasis; Pancreatic Neoplasms; Progression-Free Survival; Protein Kinase Inhibitors; Pyrazoles; Quinolines; Receptor, Transforming Growth Factor-beta Type I; Republic of Korea; Signal Transduction; Time Factors; United States

The primary cause of colorectal cancer (CRC) recurrence is increased distant metastasis after radiotherapy, so there is a need for targeted therapeutic approaches to reduce the metastatic-relapse risk. Dysregulation of the cell-surface glycoprotein podocalyxin-like protein (PODXL) plays an important role in promoting cancer-cell motility and is associated with poor prognoses for many malignancy types. We found that CRC cells exposed to radiation demonstrated increased TGFβ and PODXL expressions, resulting in increased migration and invasiveness due to increased extracellular matrix deposition. In addition, both TGFβ and PODXL were highly expressed in tissue samples from radiotherapy-treated CRC patients compared to those from patients without this treatment. However, it is unclear whether TGFβ and PODXL interactions are involved in cancer-progression resistance after radiation exposure in CRC. Here, using CRC cells, we showed that silencing PODXL blocked radiation-induced cell migration and invasiveness. Cell treatment with galunisertib (a TGFβ-pathway inhibitor) also led to reduced viability and migration, suggesting that its clinical use may enhance the cytotoxic effects of radiation and lead to the effective inhibition of CRC progression. Overall, the results demonstrate that downregulation of TGFβ and its-mediated PODXL may provide potential therapeutic targets for patients with radiotherapy-resistant CRC.

Topics: Cadherins; Cell Line, Tumor; Cell Movement; Cell Survival; Colorectal Neoplasms; Epithelial-Mesenchymal Transition; Humans; Neoplasm Metastasis; Prognosis; Pyrazoles; Quinolines; Radiation, Ionizing; RNA Interference; RNA, Small Interfering; Sialoglycoproteins; Transforming Growth Factor beta; Up-Regulation; Vimentin

Heterogeneous distribution of drug inside tumor is ubiquitous, causing regional insufficient chemotherapy, which might be the hotbed for drug resistance, tumor cell repopulation and metastasis. Herein, we verify, for the first time, that heterogeneous drug distribution induced insufficient chemotherapy would accelerate the process of epithelial mesenchymal transition (EMT), consequently resulting in the promotion of tumor metastasis. To eliminate the insufficient chemotherapy promoted metastasis, we conceived a co-delivery strategy by hydroxyethyl starch-polylactide (HES-PLA) nanoparticle, in which DOX and TGF-β receptor inhibitor, LY2157299 (LY), were administered together. In vitro and in vivo studies demonstrate that this co-delivery strategy can simultaneously suppress primary tumor and distant metastasis. Further study on immunofluorescence images of primary tumor verifies that low dose of DOX exasperates the EMT process, whereas the co-delivery nanoparticle can dramatically inhibit the progression of EMT. We reveal the impact of heterogeneous drug distribution on tumor metastasis and develop an effective co-delivery strategy to suppress the metastasis, providing guidance for clinical cancer therapy.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Doxorubicin; Drug Carriers; Drug Combinations; Embryo, Nonmammalian; Epithelial-Mesenchymal Transition; Mice; Nanoparticles; Neoplasm Metastasis; Neoplasms; Pyrazoles; Quinolines; Receptors, Transforming Growth Factor beta; Zebrafish

The observation that approximately 15% of women with disseminated breast cancer will develop symptomatic brain metastases combined with treatment guidelines discouraging single-agent chemotherapeutic strategies facilitates the desire for novel strategies aimed at outright brain metastasis prevention. Effective and robust preclinical methods to evaluate early-stage metastatic processes, brain metastases burden, and overall mean survival are lacking. Here, we develop a novel method to quantitate early metastatic events (arresting and extravasation) in addition to traditional end time-point parameters such as tumor burden and survival in an experimental mouse model of brain metastases of breast cancer. Using this method, a reduced number of viable brain-seeking metastatic cells (from 3,331 ± 263 cells/brain to 1,079 ± 495 cells/brain) were arrested in brain one week postinjection after TGFβ knockdown. Treatment with a TGFβ receptor inhibitor, galunisertib, reduced the number of arrested cells in brain to 808 ± 82 cells/brain. Furthermore, we observed a reduction in the percentage of extravasated cells (from 63% to 30%) compared with cells remaining intralumenal when TGFβ is knocked down or inhibited with galunisertib (40%). The observed reduction of extravasated metastatic cells in brain translated to smaller and fewer brain metastases and resulted in prolonged mean survival (from 36 days to 62 days). This method opens up potentially new avenues of metastases prevention research by providing critical data important to early brain metastasis of breast cancer events.

Topics: Animals; Blood-Brain Barrier; Brain; Brain Neoplasms; Cell Line, Tumor; Disease Models, Animal; Female; Humans; Mammary Neoplasms, Experimental; Mice; Mice, Nude; Microscopy, Fluorescence; Neoplasm Metastasis; Pyrazoles; Quinolines; Signal Transduction; Transforming Growth Factor beta