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O c t o b e r 1 9 - 2 0 , 2 0 1 8 | T o k y o , J a p a n
Pharma Congress 2018 & Molecular Medicine 2018
& Psychiatric Disorders 2018
Asian Journal of Biomedical and Pharmaceutical Sciences
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ISSN: 2249-622X
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Volume 8
International Conference on
PHARMACEUTICS AND NOVEL DRUG DELIVERY SYSTEMS
19
th
International Conference on
CELLULAR AND MOLECULAR MEDICINE
19
th
Annual Congress on
PSYCHIATRY AND PSYCHIATRIC DISORDERS
&
&
OF EXCELLENCE
IN INTERNATIONAL
MEETINGS
alliedacademies.comYEARS
Asian J Biomed Pharmaceut Sci 2018, Volume 8 | DOI: 10.4066/2249-622X-C3-009
PRECISION SYSTEMS MEDICINE IN UROLOGICAL TUMORS – MOLECULAR
PROFILING AND FUNCTIONAL TESTING
Khalid Saeed
University of Helsinki, Finland
Background:
Most precision cancer medicine efforts are based on the identification of oncogenic driver mutations by genome se-
quencing. We believe and have emerging evidence that this will miss therapeutic opportunities and additional technologies, such as
cell -based functional testing should be included. Pioneering studies in leukemia indicate the value of ex vivo drug testing to identify
novel, clinically actionable therapeutic opportunities.
Methods:
Using conditional re-programming technology, we established patient-derived cells (PDCs) from castration-resistant pros-
tate cancer (CRPC) and renal cell cancer (RCC) to pilot precision systems medicine in solid tumors. The PDCs were compared with
primary tumor tissue by genomic profiling and then subjected to drug sensitivity testing with >306 approved and investigational
oncology drugs.
Results:
Here, we generated both benign and malignant PDCs from prostate tissue, including six benign PDCs that were androgen re-
ceptor (AR) -negative, basal/transit-amplifying phenotype, but could re-express AR in 3D-culture. The PDCs from a CRPC patient dis-
played multiple CNAs, some of which were shared with the parental tumor. The cancer-selective drug profile for these PDCs showed
sensitivity to taxanes, navitoclax, bexarotene, tretinoin, oxaliplatin and mepacrine. RCC displays extensive intra-tumor heterogeneity
and clonal evolution. There is, however, very little information on how much this impacts drug sensitivities. Therefore, we generated
several PDCs from each RCC patient across multiple tumor regions. We verified their clonal relationship with the uncultured tumor
tissue by NGS and performed drug sensitivity profiling. The PDCs retained CNAs and driver mutations in e.g., VHL, PBRM1, PIK3C2A,
KMD5C, TSC2 genes present in the original tumor tissue. Drug testing with 461 oncology drugs identified shared vulnerability among
the multiple PDCs to pazopanib and temsirolimus that inhibit well-established renal cancer pathways VEGFR/PDGFR/FGFR and
mTOR. Importantly, however, the individual PDC from different regions in one patient also showed distinct drug response profiles,
confirming that genomic heterogeneity leads to variability in drug responses.
Conclusions:
Our aim is to generate molecular profiles and drug testing data using representative PDCs from each patient to help
clinicians in treatment decision and to facilitate the early selection of the best drug candidates for clinical development. We believe
this approach will help to personalize treatment, prioritize drugs for clinical testing, provide for intelligent selection of drug combina-
tions and improve treatment outcomes.