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therapy for a given patient’s genetic alteration profi le. The parties will utilize
M.D. Anderson’s clinical expertise to validate the discoveries and will work with
strategic partners to make drugs and diagnostics stemming from these discoveries
available to patients.
Companion Diagnostic for Viral Gene Therapy of Brain Cancer
Tova 511 (vocimagene amiretrorepvec), an injectable, and Toca FC (fl ucytosine), an
extended-release tablet, are formulations of a retroviral replicating vector for deliv-
ering a cytosine deaminase gene selectively to cancer cells. After Toca 511 spreads
through a tumor, the cancer cells expressing the cytosine deaminase gene may con-
vert the antibiotic fl ucytosine into the anticancer drug 5-FU. Tocagen, manufacturer
of Toca 511 and Toca FC, has givens Siemens Healthcare Diagnostics commercial-
ization rights to diagnostic tests for monitoring the levels of viral gene therapy for
brain cancer. Tocagen is enrolling patients for its clinical trials and will partner with
Siemens on assays used for the trials.
Drug Resistance in GBM
Despite their nearly universal activation of mammalian target of rapamycin (mTOR)
signaling, GBMs are strikingly resistant to mTOR-targeted therapy. Analysis of
GBM cell lines, patient-derived tumor cell cultures, and clinical samples from
patients in phase I clinical trials, has revealed that the promyelocytic leukemia
(PML) gene mediates resistance to mTOR-targeted therapies (Iwanami et al. 2013 ).
Direct mTOR inhibitors and EGF receptor (EGFR) inhibitors that block down-
stream mTOR signaling promote nuclear PML expression in GBMs. Genetic over-
expression and knockdown approaches demonstrate that PML prevents mTOR and
EGFR inhibitor-dependent cell death. Low doses of the PML inhibitor, arsenic tri-
oxide, abrogate PML expression and reverse mTOR kinase inhibitor resistance
in vivo, thus markedly inhibiting tumor growth and promoting tumor cell death in
mice. These results identify a unique role for PML in mTOR and EGFR inhibitor
resistance and provide a strong rationale for a combination therapeutic strategy to
overcome it.
Intratumor heterogeneity of glioblastoma multiforme is likely the key to under-
standing treatment failure or drug resistance. An integrated genomic analysis of
spatially distinct tumor fragments has been developed to uncover extensive intratu-
mor heterogeneity (Sottoriva et al. 2013 ). Phylogeny of the fragments for each
patient was reconstructed by identifying copy number alterations in EGFR and
CDKN2A/B/p14ARF as early events, and aberrations in PDGFRA and PTEN as
later events during cancer progression. Results of the study revealed patient-specifi c
patterns of cancer evolution, to enable more effective personalized treatment design.
10 Personalized Therapy of Cancer