Hypothesis/Strategy

• Identify genes downstream of AR that are important for survival of prostate cancer cells– AR signature genes– Regulators of AR signature

• Key drivers from Bayesian• Genes with overlapping perturbation signatures

• Androgen ablation therapy will select for changes downstream of AR that maintain growth signal in absence of Androgens– Genes whose expression changes with disease progression– Genes subject to CNV with disease progression

Criteria for Prioritization

• AR signature• Regulator of AR signature• Evidence for mutation/CNV

in cancer• Evidence for expression

changes/CNV changes with disease progression

2-stage Prioritization (Subjective)

• Weighting of criteria to create rank– AR sig / AR regulators / Mutation– Above + expression/CNV changes with grade

• Manual look at top 20 and select– Known genes removed– Priority for things which inhibition required– druggable

Literature:• Implicated in colon cancer through CNA/Expression• AS oligos block HBV propagation in HepG2• Mouse Gene Trap gets age-related pulmonary

emphysemaValidation• Unclear whether need to inhibit or activate to reduce growth?

Mechanism• ?

Literature:• Suppresses tumors of Hela in nude mice• Binds c-Abl and MAPK1/ERK1• Adjacent to ASCL3 on chr 11• Disrupted in congenital Mental Retardation?

Validation• Activate

Mechanism• Tumor suppressor: Growth pathways

Literature:• Phosphorylated by cell cycle kinase Aurora-C• Modulates transcriptional activity of NRs (unliganded)

• Reduced TACC1 increases RARa & TRa activity• Associated with endocrine therapy resistance in BRC• Amplified in Breast Cancer (and Prostate Cancer)

Validation• Inhibit

Mechanism• NHR signaling

Literature:• ACSL3 shows downregulation in high grade/met PRC• Important for lipid biosynthesis/regulated by PPARd• 5’ translocation partner of ETC1 in PRC• Role in Lyn transport through golgi to PM

• KD reduces Lyn export Validation• Inhibit?• Triacsin C inhibitor available

Mechanism• Metabolism: lipid biosyn

Literature:• Associated with Schizophrenia• Associated with CNV Deleted in PRC• Endocytic regulatory protein• Regulator of axon elongation in neurons

Validation• Activate?

Mechanism• ?

Literature:• Positive regulator of glycolytic function in glioblastomas• Generates acetyl-CoA+OA from citrate and CoA

• Acetyl-CoA important for biosynthesis• Regulated by AKT in lung carcinoma lines.

• siRNA resulted in growth arrest Validation• Inhibit• Hydroxycitrate inhibits

Mechanism• Metabolism: glycolysis/TCA

Literature:• TSC2 is negative regulator of mTOR pathway. • mTOR pathway activity associated with hormone-

refractory PRC

Validation• Activator• Fisetin inhibits mTOR pathway and activates TSC2

Mechanism• Growth pathways

Literature:• Global mediator of steroid receptor action in hormone-

dep cancers• FoxA1 in prostate cancer appears to act with AR in a

combinatorial fashion to regulate transcription• Low FoxA1 even with high AR predicts good prognosis• In CPRC drives G1-S transition and G2/M transition Validation

• Inhibitor

Mechanism• NHR signaling

Literature:• Inhibitor of Bax-induced apoptosis• shown to interact with broad range of partners to inhibit

many facets of apoptosis, such as ROS production, cytosolic acidification and calcium levels as well as endoplasmic reticulum stress signalling pathways

• activity is important in a large number of cancers, promoting metastasis by modulating actin dynamics

Validation• Inhibitor

Mechanism• Apoptosis

Literature:• Mutations cause metabolic disease: 3-hydroxisobutyric

aciduria

Validation• Not clear?

Mechanism• Metabolism: amino acid catabolism

Literature:• Important for stromal survival/differentiation?

Validation• inhibit

Mechanism• Stromal regulation?

Validation• Inhibit (labedipinedilol-A)

Mechanism• Apoptosis

Literature• Inhibition of human prostate cancer cells proliferation by a selective alpha1-adrenoceptor antagonist labedipinedilol-A involves cell cycle arrest and apoptosis.

Validation• Inhibit (isoform)

Mechanism• epigenetic?

Literature• Upregulation associated with leukemias•Downreg of isoform lacking transcriptional activator in CRC

Literature:• Tumor suppressor?• Region frequently lost in cancer; prostate, breast, HCC• Secreted protein associated with stromal cells?

Validation• Activate

Mechanism• Stromal?

Metabolic Pathways

IDH1

ACLY

ACSL3

Beta-oxidation of lipids

TCA Cycle

AR Signature Positively correlated gene network

AR Signature Negatively correlated gene network