Page 95 - Read Online

to CSF1R stimulates spreading and motility in macrophages from the European Union FP7 (ASSET, project number:
and their enhancement of tumor cell invasion. [131] Inhibition 259348 and LUNGTARGET, project number: 259770),
of p110δ impairs CSF-1 induced macrophage spreading the Swiss National Science Foundation (Grant 31003A-
and their invasive capacity. [132] Hence, it may be worth 146464), the Fondation FORCE, the Novartis Stiftung für
investigating whether selective inhibition of PI3Ks in the Medizinisch-Biologische Forschung, the Jubiläumsstiftung
SHH-MB subtype impairs TAM-driven tumor invasiveness. der Schweizerischen Mobiliar Genossenschaft, the Stiftung
The CD163 gene is a surface marker that is strongly zur Krebsbekämpfung, the Huggenberger-Bischoff Stiftung
expressed by tumor promoting M2 macrophages, but it zur Krebsforschung, the UniBern Forschungsstiftung, the
is not clear whether or not MB cells polarize surrounding Stiftung für klinisch-experimentelle Tumorforschung,
TAM via PI3K to enhance tumor invasion. Bern and the Berner Stiftung für krebskranke Kinder und
Jugendliche.
CLINICAL TRIALS OF KINASE
INHIBITORS IN GLIOBLASTOMA Conflicts of interest
There are no conflicts of interest.
Oncogenic kinase signaling (e.g. via the PAM pathway)
is crucial in GBM and hence attractive for targeted REFERENCES
therapy. [133,134] Unfortunately, the overall response rate
of GBMs to kinase inhibitors in clinical trials has been 1. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet
poor so far. [135] One reason for these disappointing results A, Scheithauer BW, Kleihues P. The 2007 WHO classification
of tumours of the central nervous system. Acta Neuropathol
may be inadequate trial design. Systematic flaws such as 2007;114:97-109.
small sample sizes, absent control groups and unverified 2. Johnson DR, O’Neill BP. Glioblastoma survival in the United States
drug activity have been reported in the past. [135] Therefore, before and during the temozolomide era. J Neurooncol 2012;107:359-64.
various changes in study design have been proposed to 3. Grimmer MR, Weiss WA. Childhood tumors of the nervous system as
improve the reliability of the results. Clinical trials enriched 4. disorders of normal development. Curr Opin Pediatr 2006;18:634-8.
Gajjar AJ, Robinson GW. Medulloblastoma-translating discoveries
for patients with an aberrant kinase target are likely to give from the bench to the bedside. Nat Rev Clin Oncol 2014;11:714-22.
a better picture of the overall performance of a particular 5. Cancer Genome Atlas Research Network. Comprehensive genomic
inhibitor. [136] In addition, the importance of monitoring target characterization defines human glioblastoma genes and core
inhibition and negative feedback has been shown in a phase pathways. Nature 2008;455:1061-8.
I trial in PTEN-deficient glioblastomas. [137] To improve the 6. Northcott PA, Shih DJ, Peacock J, Garzia L, Morrissy AS, Zichner
T, Stütz AM, Korshunov A, Reimand J, Schumacher SE, Beroukhim
results of clinical trials using kinase inhibitors, it appears R, Ellison DW, Marshall CR, Lionel AC, Mack S, Dubuc A, Yao Y,
necessary to set higher requirements for preclinical models Ramaswamy V, Luu B, Rolider A, Cavalli FM, Wang X, Remke M,
and to verify efficacy in a broader spectrum of GBM models Wu X, Chiu RY, Chu A, Chuah E, Corbett RD, Hoad GR, Jackman
in order to address each model’s shortcomings. Given the SD, Li Y, Lo A, Mungall KL, Nip KM, Qian JQ, Raymond AG,
fact that kinase signaling pathways are often dysregulated Thiessen NT, Varhol RJ, Birol I, Moore RA, Mungall AJ, Holt R,
Kawauchi D, Roussel MF, Kool M, Jones DT, Witt H, Fernandez-L
in parallel, it may also prove worthwhile to evaluate A, Kenney AM, Wechsler-Reya RJ, Dirks P, Aviv T, Grajkowska
combinations of different kinase inhibitors. WA, Perek-Polnik M, Haberler CC, Delattre O, Reynaud SS, Doz FF,
Pernet-Fattet SS, Cho BK, Kim SK, Wang KC, Scheurlen W, Eberhart
CONCLUSION CG, Fèvre-Montange M, Jouvet A, Pollack IF, Fan X, Muraszko KM,
Gillespie GY, Di Rocco C, Massimi L, Michiels EM, Kloosterhof
Aberrant PAM signaling can promote crucial metastatic NK, French PJ, Kros JM, Olson JM, Ellenbogen RG, Zitterbart K,
Kren L, Thompson RC, Cooper MK, Lach B, McLendon RE, Bigner
events such as angiogenesis, EMT, and modulation of DD, Fontebasso A, Albrecht S, Jabado N, Lindsey JC, Bailey S,
immune cells in both MB and GBM. Targeting the PAM Gupta N, Weiss WA, Bognár L, Klekner A, Van Meter TE, Kumabe
network may be a useful way to inhibit these often fatal T, Tominaga T, Elbabaa SK, Leonard JR, Rubin JB, Liau LM, Van
events. Understanding the molecular mechanisms and Meir EG, Fouladi M, Nakamura H, Cinalli G, Garami M, Hauser
P, Saad AG, Iolascon A, Jung S, Carlotti CG, Vibhakar R, Ra YS,
the context by which different components of the PAM Robinson S, Zollo M, Faria CC, Chan JA, Levy ML, Sorensen PH,
pathway contribute to tumor progression is a prerequisite Meyerson M, Pomeroy SL, Cho YJ, Bader GD, Tabori U, Hawkins
for the design of novel treatment strategies. Some of these CE, Bouffet E, Scherer SW, Rutka JT, Malkin D, Clifford SC, Jones
mechanisms, such as the interaction between malignant SJ, Korbel JO, Pfister SM, Marra MA, Taylor MD. Subgroup-specific
CNS cells and TME, have only recently become the focus structural variation across 1,000 medulloblastoma genomes. Nature
2012;488:49-56.
of investigation and are still incompletely understood. 7. Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol
Further studies are necessary to elucidate these 3-kinases as regulators of growth and metabolism. Nat Rev Genet
mechanisms and to determine which components of the 2006;7:606-19.
PAM pathway should be targeted to inhibit the metastasis 8. Cantley LC. The phosphoinositide 3-kinase pathway. Science
of CNS malignancies. 9. 2002;296:1655-7.
Vanhaesebroeck B, Leevers SJ, Panayotou G, Waterfield MD.
Financial support and sponsorship Phosphoinositide 3-kinases: a conserved family of signal transducers.
Trends Biochem Sci 1997.22:267-72.
Work in the author’s laboratory is supported by grants 10. Lemmon MA. Membrane recognition by phospholipid-binding

Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ March 11, 2016 ¦ 85