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The mitogen-activated protein kinase (MAPK)-interacting kinases 1 and 2 (MNKs 1/2) and their downstream target eIF4E, play a role in oncogenic transformation, progression and metastasis. These results provided rationale for development of first MNKs inhibitors, currently in clinical trials for cancer treatment. Inhibitors of the MNKs/eIF4E pathway are also proposed as treatment strategy for inflammatory conditions. Here we present results of optimization of indazole-pyridinone derived MNK1/2 inhibitors among which compounds 24 and 26, selective and metabolically stable derivatives. Both compounds decreased levels of eIF4E Ser206 phosphorylation (pSer209-eIF4E) in MOLM16 cell line. When administered in mice compounds 24 and 26 significantly improved survival rates of animals in the endotoxin lethal dose challenge model, with concomitant reduction of proinflammatory cytokine levels – TNFα and IL-6 in serum. Identified MNK1/2 inhibitors represent a novel class of immunomodulatory compounds with a potential for the treatment of inflammatory diseases including sepsis.

Background Stimulator of Interferon Genes (STING) is a major player in the activation of robust innate immune response leading to initiation and enhancement of tumor-specific adaptive immunity. Several clinical and pre-clinical programs have shown that activation of the STING pathway triggers immune-mediated antitumor response. Although vast majority of programs focus on development of analogues of the endogenous STING ligands, their chemical nature and stability often limit their use to local administration. Herein, we present recent results from the development of our selective non-nucleotide, non-macrocyclic, small molecule direct STING agonists, suitable for systemic administration, characterized by improved activity in human immune cells. Methods Binding to recombinant STING protein was examined using FTS, MST, FP and crystallography studies. Phenotypic screen was performed in THP-1 Dual reporter cells. Mouse bone marrow-derived dendritic cells (BMDC) were obtained from C57BL/6 mice and differentiated with mIL-4 and mGM-CSF. STING agonists were administered into BALB/c mice and cytokine release was measured in plasma. Additionally, mice were inoculated with CT26 murine colon carcinoma or EMT6 murine breast carcinoma cells and the compound was administered, followed by the regular tumor growth and body weight monitoring. Results Ryvu’s small-molecule agonists demonstrate strong binding affinity to recombinant STING proteins across all tested species. The compounds bind to all human STING protein variants and trigger pro-inflammatory cytokine release from human immune cells regardless of the STING haplotype. Moreover, new generation of developed agonists show significantly improved binding to human protein as well as in vitro activity on human cells. Systemic, intravenous in vivo administration leads to a dose-dependent upregulation of STING-dependent pro-inflammatory cytokines, which results in a dose-dependent antitumor efficacy observed in CT26 and EMT6 mouse cancer models, leading to complete tumor remissions in all treated animals. Furthermore, observed efficacy is accompanied by development of a lasting immunological response demonstrated by lack of tumor engraftment or a delayed tumor growth in cured animals challenged with repeated inoculation of cancer cells. Conclusions New generation Ryvu’s STING agonists are strong and selective activators of STING-dependent signaling in both mouse and human immune cells promoting anti-tumor immunity. Treatment with Ryvu’s small-molecule STING agonists leads to engagement of the immune system which results in a complete tumor remission and development of immunological memory of the cancer antigens. The compounds show good selectivity and ADME properties enabling development for systemic administration. In addition developed compounds maintain small functional handles amenable to linker attachment making the series suitable for versatile development as single agents, for combinations with immunotherapies or as targeted agents.

Many plant species can reproduce by both sexual and vegetative means. Clonal diversity and degree of intermingling of clones in the vegetative reproductive mode can influence the mating and fertility of individuals. The aim of the study was to assess the clonal structure and its potential influence on gene flow and generative reproduction efficiency in six endangered Betula humilis populations from the southwestern margin of the species range. Analyses of seven microsatellite loci revealed 86 genets among 522 samples. In general, the phalanx strategy dominated in the populations considered, as 76% of ramets shared the same genotype with their closest neighbour. Nevertheless, substantial clonal and genetic diversities and high contribution of unrelated individuals in all B. humilis stands suggest that panmictic pollination prevails. On the other hand, positive and significant relationships between genetic and geographic distances in the two populations could be a consequence of biparental inbreeding resulting from the pollen and seed flow limitations. The seed germination capacity was very low (2.70%); however, the populations characterised by the lowest and highest values of clonal diversity parameters did not differ significantly in the number of germinated seeds, which indicates that clonality is not responsible for seed production failure.

Background: Hematopoietic progenitor kinase 1 (HPK1, MAP4K1) is a member of the serine/threonine MAP4K family predominantly expressed in hematopoietic cell lineages which plays a pivotal role in the negative regulation of the signaling cascade triggered by T cell receptor engagement. Inhibition of its activity promotes secretion of IL-2, T cell maturation, and proliferation. It has been also suggested that inhibition of HPK1 may hyperactivate both B cells and dendritic cells via hampering HPK1- mediated negative feedback mechanisms involved in BCR regulation and enhancement of antigen presenting capability of dendritic cells. Suppression of the TCR inhibitory mechanisms with small molecule HPK1 inhibitors might constitute a novel approach in tumor immunotherapy which enhances neoantigen recognition and boosts immune responses of T and B lymphocytes against cancer cells. Thus, small molecule HPK1 inhibitors may provide additional benefit for patients subjected to existing immunotherapies. Methods: Inhibition of HPK1 was assessed by biochemical assay with recombinant human and mouse protein. Small molecule inhibitors were tested in biochemical assay on selected anti- and off-targets and profiled against a broad kinase panel. Phosphorylation of serine 376 on SLP-76 adaptor protein and specific TCR activation-related markers upon HPK1 inhibition was monitored by either Western Blotting or flow cytometry in human and murine T-cells. IL-2 release was measured in human PBMCs and mouse splenic T cells. PBMC cells were activated and exposed to compounds in the presence of PGE-2, followed by IL-2 release measurement. Mice were challenged with the compounds and pharmacodynamic biomarkers were evaluated through flow cytometry and AlphaLisa. Results: Small molecule Ryvu HPK1 inhibitors block kinase activity of recombinant mouse and human protein with sub-nanomolar IC50 values. Ryvu compounds selectively engage downstream biomarkers in human and murine T cells. While inhibiting phosphorylation of serine 376, Ryvu HPK1 inhibitors do not affect activatory phosphorylation of specific phosphotyrosine residues of SLP-76 in human or mouse CD3+ T cells. Ryvu compounds overcome PGE-2 induced resistance following TCR activation in human PBMCs, and mouse CD3+ T cells, inducing IL-2 release. Ryvu compounds have good physicochemical properties and good overall selectivity. In vivo activity and target engagement have been confirmed in the model with anti-CD3 antibody infusion. Conclusion: Pharmacological inhibition of HPK1 kinase activity has strong potential to become a novel immunomodulatory approach for cancer treatment. Citation Format: Maciej Kujawa, Eliza Zimoląg, Michał Gałęzowski, Paweł Guzik, Agata Dudek, Andrzej Gondela, Marcin Nowogródzki, Marianna Girardi, Kostiantyn Krolenko, Marta Bugaj, Sylwia Sudoł, Agnieszka Gibas, Joanna Szeremeta-Spisak, Aneta Bobowska, Magdalena Zastawna, Przemysław Wyrębek, Nicolas Boutard, Aleksandra Więckowska, Wojciech Jasnosz, Wojciech Schonemann, Karol Zuchowicz, David Synak, Urszula Kulesza, Oleksandr Leventes, Mateusz Świrski, Sujit Sasmal, Karolina Gluza, Patryk Kret, Mateusz Ogórek, Kinga Michalik, Katarzyna Banaszak, Adrian Podkowa, Katarzyna Wnuk-Lipińska, Monika Dobrzańska, Peter Littlewood, Krzysztof Brzózka, Anna Bartosik, Stefan Chmielewski. Development and characterization of small molecule HPK1 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1281.

Background. Stimulator of interferon genes, known as STING, is an intracellular sensor of nucleic acids and one of key regulators in activating the innate immune response. Employing synthetic STING agonists has been shown to promote immune-mediated antitumor response in preclinical animal models. Ryvu is developing small-molecule STING agonists suitable for systemic administration. Herein we present unpublished results from characterization of the new generation of our agonist series with significantly improved potency on human immune cells. Methods. Binding to recombinant STING protein was examined using Fluorescence Thermal Shift and Fluorescence Polarisation and was confirmed by X-ray crystallography. Primary screen was performed in THP-1 Dual reporter cells and selectivity was confirmed in THP-1 reporter cells with knocked out STING or expressing varying STING variants. T cell viability and proliferation was assessed by flow cytometry using activated, human T cells exposed to STING agonists. STING pathway activation pattern in cells treated with Ryvu's molecules was confirmed using Western blot analysis. BALB/c mice were injected with compounds and the levels of cytokine release were measured in the plasma. Mice were inoculated with CT26 or EMT6 tumor cells and the compound was administered intravenously followed by the regular monitoring of tumor growth. Results. New generation Ryvu STING agonists are strong binders of human STING protein. Ryvu's compounds show high cellular potency inducing cytokine production in human immune cells at low nM range. Moreover, high activity of developed agonists is maintained irrespective of the natural human STING variant as seen in THP-1 reporter cells as well as in human primary immune cells. High cellular potency of developed compounds also translates into efficacy observed in vivo, where systemic intravenous administration leads to significant tumor growth inhibition and complete tumor regressions in mouse syngeneic models. Conclusion. Ryvu has developed a new generation of potent, direct and selective small-molecule STING agonists. The compounds are characterized by drug-like properties and high in vitro potency on par or outperforming known references. Ryvu agonists are suitable for systemic administration and allow to achieve excellent antitumor efficacy. Taken together, the promising results suggest that the developed series holds high potential for improving immunotherapy in cancer patients. Citation Format: Maciej Krzysztof Rogacki, Stefan Chmielewski, Jolanta Mazurek, Magdalena Zawadzka, Katarzyna Wnuk-Lipińska, Kamil Kuś, Katarzyna Wójcik-Jaszczyńska, Aleksandra Poczkaj, Łukasz Dudek, Wojciech Schonemann, Urszula Głowniak-Kwitek, Marcin Leś, Marek Wronowski, Tushar Mahajan, Urszula Kulesza, Magdalena Zastawna, David Synak, Karol Zuchowicz, Karolina Gluza, Katarzyna Banaszak, Karolina Wiatrowska, Izabela Strojny, Mirosława Gładysz, Justyna Jabłońska, Ewelina Gabor-Worwa, Monika Dobrzańska, Raghuram Tangirala, Peter Littlewood, Krzysztof Brzózka. New generation of STING agonists: Development and characterization of a novel series of systemic immunomodulators with improved potency [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1280.

Background: Synthetic lethality is one of the most innovative approaches for selective targeting of cancer cells with defined genetic background. SMARCA2 and SMARCA4 are two mutually exclusive helicase/ATPase catalytic subunits belonging to SWI/SNF chromatin remodeling complex. It is estimated that one in five tumors possess a mutation in proteins of this complex. The Cancer Genome Atlas (TCGA) and the Catalog of Somatic Mutation in Cancer (Cosmic) shows that SMARCA4 is one of the most mutated genes in lung, colorectal, breast, melanoma and CNS tumors. Herein, we present development of a potent and selective SMARCA2 degrader, structurally unrelated to known chemotypes with first in class potential selectively targeting SMARCA4 mutant cells. Methods: ADP-Glo assay was used to identify SMARCA2 inhibitors through HTS. Binding was confirmed using MST, FTS and SPR methods. Biochemical and biophysical investigation guided rational optimization. Identified ligands were used to build a hybrid PROTAC by linking to a ligand for the E3 ligase. Western blotting was used to assess degradation efficiency and selectivity. Target engagement was confirmed using qPCR and AlphaLISA methods. On target activity was confirmed using SMARCA4 isogenic cells and a panel of SMARCA4 WT and mutant cell lines. Results: High throughput screening allowed identification of novel inhibitors of SMARCA2 ATPase activity. Medicinal chemistry efforts improved potency and affinity to the target over 100 fold. Target engagement was confirmed using biophysical methods and biomarker modulation. Proprietary ligand was used to build a hybrid PROTAC. Western blotting confirmed selective and long-lasting degradation of SMARCA2. Co-treatment with Epoxomicin confirmed proteasomal dependent degradation of targeted protein. Specific SMARCA2 depletion in SMARCA4 mutated cancer cell lines induced apoptosis, growth inhibition and cell death. Observed mechanism of action is consistent with a phenotype seen with perturbation through inhibition of ATPase activity of SMARCA2 and genetic knock-down. Conclusion: Treatment with Ryvu's PROTACs led to selective, proteasomal dependent degradation of SMARCA2 protein and in consequence to a targeted cell death of SMARCA4 mutated cancers. Fine-tuning of available compounds will allow for proof-of-concept experiments in animal models as a single agent or in combinations with radio- or immuno-therapies. Citation Format: Andrzej Mazan, Anna Wróbel, Agnieszka Dreas, Adam Radzimierski, Kinga Michalik, Anna Kowal, Katarzyna Wiklik, Katarzyna Wnuk-Lipińska, Paulina Niedziejko, Kamila Kozłowska, Magdalena Łośko, Joanna Szczęśniak, Agnieszka Sroka-Porada, Justyna Martyka, Urszula Kulesza, Karol Zuchowicz, Magdalena Zastawna, Jose Alvarez, Luigi Stasi, Peter Littlewood, Tomasz Rzymski, Krzysztof Brzózka. Development of novel, selective SMARCA2 (BRM) degraders for treatment of SMARCA4 (BRG1) mutated tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3656.

Continuing the structure-activity relationship studies in the vitamin D area, we designed and synthesized novel C-9 substituted calcitriol analogues, possessing different nonpolar groups at this position. 9α-Methyl-1α,25-(OH)2D3, both epimers of 9-methylene-10,19-dihydro-1α,25-(OH)2D3 as well as the parent vitamin with the "reversed" triene system, 9-methylene-19-nor-1α,25-(OH)2D3, were obtained from the previtamin D precursors, constructed by either Suzuki-Miyaura, Sonogashira, or Stille couplings of the corresponding A- and C,D-ring fragments. An alternative synthetic path, leading to the latter vitamin and its homologue with 9-ethylidene group, involved formation of dienynes as precursors of the respective 19-norprevitamin D compounds. 9β-Methyl-19-nor-1α,25-(OH)2D3 was prepared by homogeneous hydrogenation with Wilkinson catalyst, and this analogue was found to be the most active in vitro. Moreover, 9α-methyl-1α,25-(OH)2D3 and 9-methylene-19-nor-1α,25-(OH)2D3 showed some in vitro activity, however, the in vivo assays indicated only weak calcemic potency of these compounds in the intestinal calcium transport.

9-Alkylidene analogs of 19-nor-1α,25-(OH) 2 D 3 were synthesized, possessing a ‘reversed’ triene system compared to the natural hormone. The conjugated triene moiety of the novel analogs was constructed by coupling an enyne anion, representing an A-ring synthon, with a 9α-substituted Grundmann ketone derivative. Regioselective dehydration followed by semihydrogenation under Lindlar conditions, provided the desired 9-alkylated 19-norprevitamins which were thermally isomerized to the corresponding 9-methylene and 9-ethylidene analogs of 19-norcalcitriol. It was established that only the former compound had significant binding affinity to the full-length recombinant rat vitamin D receptor. The remaining in vitro studies show very low activity of both analogs. This article is part of a Special Issue entitled ‘Vitamin D Workshop’.

Two new sulfur-containing cholane derivatives were obtained from cholic acid: 3α-mercapto-5β-cholane-7α,12α,24-triol 2 and its C(3)–C(3′) disulfide dimer 3 as a potential supramolecular host.

Over-activation of the serine synthesis pathway, upregulation of SHMT2 has been described in over 20% of solid tumors (e.g. breast, lung, colorectal cancers). Such cancer cells are highly dependent on serine. Serine hydroxymethyltransferase (SHMT) plays a key role in a so-called one-carbon pathway, a group of biochemical reactions involved in amino acid metabolism. SHMT catalyzes the conversion of serine to glycine and also plays a role in the folate (vitamin B9) cycle. Antagonists of folate metabolism or antifolates are an established chemotherapy in certain cancers. Folate antagonism disrupts cell division, DNA/RNA synthesis and protein synthesis. Pemetrexed (for non-small cell lung carcinoma, mesothelioma) and methotreaxate (for autoimmune conditions like rheumatoid arthritis and certain cancers) are two well established and effective antifolates. The main drawback with antifolates in cancer treatment, however, is the development of resistance. In this study we report development of a series of small molecule SHMT1/2 inhibitors. Synthetized compounds exert potency in SHMT1/2 biochemical assay as well as in cellular assay (measured by the C13 serine to glycine conversion) with the low nanomolar range. Therapeutic effect of the compounds was investigated in the panel of cancer cell lines with different genetic background as well as with different SHMT2 levels. We identified several cell lines in which tested compounds inhibited cancer cell grow with nM GI50 values. Taken together, presented data supports our rationale for using SHMT1/2 inhibitors as a novel and interesting approach for the cancer therapy. Citation Format: Anna Bartosik, Pawel Guzik, Marta Sowinska, Karolina Gluza, Marcin Krol, Anna Wrobel, Agnieszka Dreas, Faustyna Iwanska, Magdalena Zastawna, Urszula Kulesza, Nicolas Boutard, David Schultz, Justyna Wujkowska, Karolina Pyziak, Agnieszka Sroka-Porada, Agnieszka Przybylowicz, Agnieszka Adamus, Magdalena Sieprawska-Lupa, Przemyslaw Golik, Piotr Kowalczyk, Krzysztof Brzozka, Tomasz Rzymski, Mateusz Nowak. Discovery of novel SHMT small molecule inhibitors for cancer treatment [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 3516.

The UV-induced photochemical reaction of 1α,25-dihydroxy-9-methylene-19-norvitamin D3 has been investigated. The pentacyclic structure of the isolated product has been unequivocally established by X-ray crystallographic analysis. The possible reaction paths of the examined photochemical transformation are discussed. Biological in vivo and in vitro tests proved that the photoproduct is devoid of calcemic activity.

Primary cultures of human bone and vascular cells respond to vitamin D treatment by modulation of cell proliferation measured by DNA synthesis (DNA) and energy metabolism measured by creatine kinase specific activity (CK) via binding to vitamin D receptors (VDR) which are expressed in these cells. Vitamin D compounds also modulate the response to estradiol-17β (E₂) and the expression mRNAs of estrogen receptors (ERα and ERβ), VDR, 25-hydroxy vitamin D₃ 1-α hydroxylase (1OHase) and lipoxygenases (12LO and 15LO). We now compared our newly synthesized analog: 1α,25-dihydroxy-9-methylene-19-norvitamin D₃ JK152 (JK), on bone and vascular cells compared to other analogs. Human bone cell line SaOS₂ respond to JK by increased DNA and stimulated CK dose-dependently, similar to the less-calcemic analogs CB 1093 (CB) and EB 1089 (EB). JK also up-regulated the response to E₂ in terms of DNA and CK. JK inhibited DNA synthesis and increased CK in primary human vascular smooth muscle cells (VSMC) dose-dependently similar to EB and CB. JK up regulated the response to E₂ in terms of CK with no effect on DNA. JK similar to CB and EB stimulated mRNA expression of VDR and ERα, 12LO and 15LO, with no effect on ERβ and 1OHase mRNA expression in SaOS₂ measured by real time PCR. Similar treatments of VSMC with JK, CB and EB stimulated 12LO and 15LO, VDR and ERα mRNA expression with no effect on ERβ and 1OHase mRNA expression. The results presented here demonstrate that the new vitamin D less-calcemic analog JK is similar to other analogs in its effects on human cultured cells and therefore may be used in combined hormone replacement treatment (HRT) both in vitro and in vivo.

Convergent syntheses of three new analogues of 1α,25-dihydroxyvitamin D 3 with α-hydroxyalkyl substituents at C12 ( 4a – c ) are described. The A-ring and triene system of each analogue were assembled by a tandem Pd-catalysed intramolecular cyclization and Suzuki–Miyaura coupling process. The stereoselective introduction of substituents at C12 was achieved by Johnson–Claisen rearrangement on allylic alcohol 15 as the key step. This article is part of a Special Issue entitled ‘Vitamin D Workshop’.

Herewith, we report development of small molecule inhibitors of MNK1 and MNK2 kinases and their cellular activity. MNK1 and 2 are MAP kinase-interacting kinases are activated by RAS and MAPK signaling pathways, and are involved in regulation of translation. Both kinases phosphorylate translation initiation factor eIF4e on a conserved serine 209. eIF4E can contribute to the oncogenic transformation both in vitro and in vivo and is highly expressed in diverse types of cancer. Interestingly, mice that lack both Mnk1 and Mnk2 do not have any apparent phenotype. Recently first dual MNK1/MNK2 inhibitors have entered clinical trials as a combinational therapy with docetaxel in NSCLC. SEL201 is a series of small molecule inhibitors which inhibit activity of both MNK1 and MNK2 in a low nM range and high selectivity confirmed in kinome panels. Analysis of SEL201 cellular activity indicated potent inhibition of eIF4e Ser209 in vitro in cancer cells and in vivo after oral administration in xenograft tumors. Repressed phosphorylation of eIF4e resulted in impaired translation of several proteins involved in metastasis and activation of immune cells. High potency, selectivity and favorable ADME/PK profile indicates that SEL201 inhibitors would be useful tools in probing molecular consequences of eIF4e Ser209 inhibition in cancer cells. SEL201 in vitro and in vivo activities on viability and metastasis will be presented in cellular and in vivo models of solid tumors and hematological malignancies. SEL201 series is further developed as a cancer therapy with a good therapeutic window. Citation Format: Tomasz Rzymski, Agnieszka Dreas, Ewelina Wincza, Charles-Henry Fabritius, Urszula Kulesza, Katarzyna Kucwaj- Brysz, Mariusz Milik, Aniela Gołas, Renata Windak, Eliza Żyłkiewicz, Anna Wróbel, Maciej Sułkowski, Krzysztof Brzózka. Repression of tumor survival pathways by novel and selective inhibitors of MNK1 and MNK2 kinases in cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C194.

Herewith, we report development of small molecule inhibitors of MNK1 and MNK2 kinases and their cellular activity. MNK1 and 2 are MAP kinase-interacting kinases that are activated by RAS and MAPK signaling pathways and are involved in regulation of translation. Both kinases phosphorylate translation initiation factor eIF4e on a conserved serine 209 residue. eIF4E can contribute to the oncogenic transformation both in vitro and in vivo and is highly expressed in various tumor types. Interestingly, mice that lack both MNK1 and MNK2 do not have any apparent phenotype, which is promising for the therapeutic window of MNK1/2 inhibitors. SEL201 is a series of small molecule inhibitors which inhibit activity of both MNK1 and MNK2 in a low nM range. Selected compounds were tested on the kinome panels and indicated MNK1 and MNK2 as primary kinase targets. SEL201 compounds caused dose dependent inhibition of phosphorylation of eIF4e at Ser209 in various cancer cell lines at concentrations Citation Format: Tomasz Rzymski, Malgorzata Szajewska-Skuta, Adrian Zarebski, Kamil Sitarz, Lukasz Sapala, Malgorzata Zurawska, Magdalena Salwinska, Renata Windak, Ewa Trebacz, Joanna Daniel-Wojcik, Radoslaw Obuchowicz, Bozena Winnik, Ewelina Wincza, Urszula Kulesza, Katarzyna Kucwaj-Borysz, Mariusz Milik, Agnieszka Dreas, Krzysztof Brzozka. Repression of tumor survival pathways by novel and selective inhibitors of MNK1 and MNK2 kinases in glioblastoma and colorectal cancer. [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 755. doi:10.1158/1538-7445.AM2014-755