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Background Although the epidermal growth factor receptor (EGFR) is a frequent oncogenic driver in glioblastoma (GBM), efforts to therapeutically target this protein have been largely unsuccessful. The present pre-clinical study evaluated the novel EGFR inhibitor WSD-0922. Methods We employed flank and orthotopic patient derived xenograft (PDX) models to characterize WSD-0922 and compare its efficacy to erlotinib, a potent EGFR inhibitor that failed to provide benefit for GBM patients. We performed long-term survival studies and collected short-term tumor, plasma, and whole-brain samples from mice treated with each drug. We utilized mass spectrometry to measure drug concentrations and spatial distribution and to assess the impact of each drug on receptor activity and cellular signaling networks. Results WSD-0922 inhibited EGFR signaling as effectively as erlotinib in in vitro and in vivo models. While WSD-0922 was more CNS penetrant than erlotinib in terms of total concentration, comparable concentrations of both drugs were measured at the tumor site in orthotopic models, and the concentration of free WSD-0922 in the brain was significantly less than the concentration of free erlotinib. WSD-0922 treatment provided a clear survival advantage compared to erlotinib in the GBM39 model, with marked suppression of tumor growth and most mice surviving until the end of the study. WSD-0922 treatment preferentially inhibited phosphorylation of several proteins, including those associated with EGFR inhibitor resistance and cell metabolism. Conclusions WSD-0922 is a highly potent inhibitor of EGFR in GBM, and warrants further evaluation in clinical studies.

Coconut [Cocos nucifera L.] is often called “the tree of life” because of its many uses in the food, beverage, medicinal, and cosmetic industries. Currently, more than 50% of the palms grown throughout the world are senile and need to be replanted immediately to ensure production levels meet the present and increasing demand for coconut products. Mass replanting will not be possible using traditional propagation methods from seed. Recent studies have indicated that in vitro cloning via somatic embryogenesis is the most promising alternative for the large-scale production of new coconut palms. This paper provides a review on the status and prospects for the application of somatic embryogenesis to mass clonal propagation of coconut.

Objective: Osteosarcoma (OS) is a common bone cancer that usually influences children. Metastasis and recurrence are the main reasons for the poor prognosis. In this study, we investigated the functions and mechanisms of KCNQ1 opposite strand/antisense transcript 1 (KCNQ1OT1) in OS. Methods: Cell viability and proliferation were detected using the CCK-8 assay and the 5-Ethynyl-2’-deoxyuridine (EdU) assay. Wound-healing assays, transwell assay and flow cytometry were used to identify cell migration, invasion, and apoptosis, respectively. The relationship among KCNQ1OT1, miR-154-3p, and KLF12 was verified by luciferase reporter assay and restricting protein immunoprecipitation (RIP) assay. Xenograft models were established to confirm the function of KCNQ1OT1 in vivo. Results: The expression of KCNQ1OT1 was higher in OS than in non-tumor tissues and cells. Knockdown of KCNQ1OT1 could reduce OS cell proliferation, migration, and invasion and promoted cell death. Mechanistically, KCNQ1OT1 contributed to OS formation by acting as a competitive endogenous RNA (ceRNA) and influencing miR-154-3p expression. Furthermore, we confirmed that miR-154-3p affected KLF12 expression through binding the 3’UTR region. Finally, rescue experiments determined that KCNQ1OT1 exerted major roles in OS through the miR-154-3p/KLF12 axis. Conclusion: In conclusion, our research explains the mechanism of KCNQ1OT1 in OS progression, which could serve as a new therapeutic target.

ATM (ataxia telangiectasia mutated) kinase, activated by DNA double-strand breaks, promotes DNA repair as well as activates DNA damage checkpoint and plays a key role for resistance to radiotherapy and chemotherapy. ATM function loss confers hypersensitivity to ionizing radiation evidenced by ataxia-telangiectasia (A-T) cells. Thus, pharmacological inhibition of ATM kinase is expected to suppress DSB DNA repair, block checkpoint controls and enhance the therapeutic effect of radiotherapy and other DNA double-strand breaks-inducing chemotherapy. Herein, we report a discovery of a potent, selective, orally bioavailable, and brain penetrable ATM inhibitor WSD0628, as a radiosensitizer for GBM and metastatic CNS tumors with IC50 against ATM < 1nM with high selectivity ( >400 folds) for ATR and DNA-PK. WSD0628 is highly selective over other kinases. In-vitro MDCKII transfected cells and Caco-2 assays have shown that WSD0628 is highly permeable and not a substrate of P-gp or BCRP, two main efflux transporters expressed on human BBB. Preclinical CNS PK studies in rat and mouse confirmed good brain penetration of WSD0628 with Kp,uu,brain and Kp,uu,csf > 0.3. Significant prolongation of overall survival for mice bearing GBM PDX intracranial model was achieved by treatment with WSD0628 (5mpk, QD) combo with radiation. Moreover, WSD0628 shows low PK variation liability without aldehyde oxidase (AO) metabolism, low hERG liability ( >30 uM), and good safety window based on DRF studies. Taken together, our data provide a good rationale for WSD0628 to be developed toward clinic combo with radiation for the treatment of patients with GBM and cancers with CNS metastasis.

The VEGF pathway has emerged as an important target for cancer therapy by blocking the development of malignant neovasculature, thus to reduce oxygen availability to the tumor and decrease its growth. Anti-VEGF agents have been approved for several malignancies, such as GBM, NSCLC, mBC, CRC, OC, etc with satisfactory performance to extracranial lesions, but not in intracranial lesions. Insufficient penetration across BBB is one of factors limiting intracranial anti-tumor activity for those anti-VEGF agents, due to either large molecule weight or being substrate of BBB efflux transporters. The incidence of BM is increasing, and surgery/radiotherapy are the most common options for the management of BM. Patients with BM have a very poor prognosis and short survival. To address the role of anti-angiogenesis in the treatment of BM, a BBB penetrable, selective and potent VEGFR2 inhibitor WSD1227 is discovered with IC(50) against VEGFR1/2/3 at 0.69/0.35/0.41nM versus against other targets such as PDGFR(α) IC(50) 22.9nM, PDGFR(β) IC(50) 19.4nM, cKit IC(50) 383nM, FLT3 IC(50) 555 nM and CSF1R IC(50) 1062nM. In-vitro MDCKII transfected cell assays demonstrated WSD1227 is not a substrate of P-gp or BCRP, two main efflux transporters on human BBB. Preclinical CNS PK studies confirmed brain penetration of WSD1227 with K(p,uu,brain) close to unity, thus not exacerbating VEGF related systemic toxicities. WSD1227 possessed superior PK profile with sufficient free PK exposure to achieve target engagement in mice. Treatment of tumor bearing mice in GBM, NSCLC, CRC and OC xenograft models with WSD1227 resulted in significant tumor growth inhibition. Predicted human PK properties are very promising to offer sufficient target engagement in clinic. Taken together, our data provide a good rationale for WSD1227 to be developed toward clinic to investigate anti-angiogenetic therapies for management of patients with primary or metastatic brain tumors.

Aberrant EGFR signaling caused by mechanisms of overexpression, mutation, or autocrine activation contributes for oncogenesis by inducing cell proliferation and resisting apoptosis. In patients with GBM, an overall frequency of 25–64% mutation is EGFRvIII (exon2-7 deletion). In patients with NSCLC harboring active EGFRm+(Del19 and L858R), up to 65% brain/leptomeningeal metastasis develop ultimately after EGFR TKIs treatment. Current approved EGFR TKIs have demonstrated limited therapeutic efficacy against CNS tumors due to insufficient BBB penetration and/or poor activity against EGFRm+ such as EGFRVIII. The occurrence of GBM and rate of CNS metastases of NSCLC are increasing, thus there is a high unmet medical need for the development of a BBB penetrable EGFR inhibitor (common tumor drivers in the brain: EGFRVIII/Del19/L858R) to clinic. Herein, we report a discovery of brain penetrable EGFR inhibitor WSD0922 for GBM and NSCLC CNS metastasis with IC(50) against EGFRm+ ex-vivo GI(50) in GBM tissues with EGFRvIII is In-vitro MDCKII transfected cells and Caco-2 assays have shown that WSD0922 is highly permeable (61x10(-6) cm/s) and not a substrate of P-gp or BCRP, two main efflux transporters expressed on human BBB. Preclinical CNS PK studies confirmed good brain penetration of WSD0922 with K(p,uu,brain) close to unity. Significant TGI or regression for mice bearing GBM PDX model with EGFRVIII was achieved by treatment with WSD0922. Moreover, treatment of mice bearing PC-9 (Del19 in NSCLC) in both subcutaneous and intracranial models with WSD0922 resulted in dose dependent TGI or regression with statistically significant survival benefit. Predicted human PK properties are very promising to offer sufficient target engagement in clinic. Taken together, our data provide a good rationale for WSD0922 to be developed toward clinic for the treatment of patients with GBM and CNS metastasis of NSCLC harboring EGFRm+.

Anti-angiogenesis has been proved to be a good strategy for cancer treatment (such as in GBM, NSCLC, mBC, CRC, OC, etc.) with satisfactory performance to extracranial lesions, but not in intracranial lesions. Insufficient penetration across BBB could be one of factors limiting intracranial activity for those approved anti-VEGF agents. There is a need to develop a BBB penetrable VEGFR inhibitor to clinic to assess the efficacy and safety. Here we report that WSD1227, a novel, selective VEGFR inhibitor, displays potent activity, excellent CNS penetration and preclinical safety and efficacy. The IC50 of WSD1227 against VEGFR1/2/3 at 0.69/0.35/0.41nM versus against other targets such as PDGFRα IC50 22.9nM, PDGFRβ IC50 19.4nM, cKit IC50 383nM, FLT3 IC50 555 nM and CSF1R IC50 1062nM. WSD1227 treatment resulted in significant anti-tumor activity in VEGF related extracranial and intracranial mice models, with superior efficacy than bevacizumab. There is no increased risk of CNS hemorrhage in intracranial tumor bearing mice treated with WSD1227. In addition, WSD1227 is predicted to be CNS penetrable with decent PK in human. Taken together, our data provide a good rationale for WSD1227 to be developed toward clinic to investigate anti-angiogenetic therapies for management of patients with primary or metastatic brain tumors. Citation Format: Jinqiang Zhang, Wei Zhong, Zhihua Mu, Claire Sun. WSD1227: A BBB penetrable VEGFR small molecule for the treatment of primary and metastatic brain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2203.

Occurrence of brain metastases (BM) has been reported in ~10% cancer patients as a later manifestation of the disease with incidence depending on the type of primary tumors1: about 20~40% in NSCLC and BC2,3 and significant tumor growth inhibition (TGI). Similar TGI was observed in SKOV-3 bearing mice, an OC xenograft in both SC and intracranial models. No toxicity was observed in the animals during the treatment. Moreover, predicted human PK properties are very promising to offer sufficient target engagement at a pretty low dose in clinic. Taken together, our data provide a good rationale for WSD1227 to be developed toward clinic for the treatment of patients with BM whose primary tumors have already been controlled well by systemic therapies. Citation Format: Jinqiang Zhang, Wei Zhong, Zhihua Mu, claire sun. WSD1227: A novel, oral bioavailable, brain penetrable and reversible VEGFR inhibitor for the treatment of primary and metastatic brain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4793.

Epidermal growth factor receptor (EGFR) is a cell surface protein that regulates normal cellular growth in tissues of epithelial origin. Des-regulated EGFR signaling (caused by mechanisms of overexpression, mutation, autocrine activation) contributes for oncogenesis by inducing cells proliferation and resisting apoptosis. In patients with NSCLC, activating mutants (EGFRm+) occur within exon 18-21 with increased EGFR activity. About 90% of these mutations (G719x, exon 19 deletions and exon 21 mutation) are sensitizing EGFRm+. EGFR TKIs have shown good performance in clinic for systemic NSCLC anchoring EGFRm+. However, up to 65% of NSCLC patients will develop brain metastasis (BM) ultimately. Current approved EGFR TKIs are not so effective for BM due to limited brain penetration as they are substrates of P-gp or BCRP, two main efflux transporters expressed on human BBB. In patients with GBM, the most common mutation is EGFRvIII (exon2-7 deletion) with an overall frequency of 25–64%. Current EGFR TKIs are ineffective in GBM treatment probably due to resistance caused by EGFRvIII as well as limited brain penetration. One-year survival of GBM patients is approximate 43%. Herein, we report a discovery of brain penetrable EGFR inhibitor WSD0922 for NSCLC BM and GBM with IC50 against EGFRm is WSD0922. No toxicity was observed in the animals during the treatment. Predicted human PK properties are very promising to offer sufficient target engagement in clinic. Taken together, our data provide a good rationale for WSD0922 to be developed toward clinic for the treatment of patients with BM of NSCLC or GBM harboring EGFRm+. Citation Format: Wei Zhong, Jinqiang Zhang, Zhihua Mu, Claire Sun. WSD0922: A novel, oral bioavailable, brain penetrable and reversible EGFRm+ inhibitor for the treatment of primary and metastatic brain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4786.