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Title: Prostate Cancer 101 Cell 616


1
Prostate Cancer 101Cell 616
  • Joshi Alumkal, MD
  • Assistant Professor of Medicine
  • May 6, 2009

2
Outline
  • Background on prostate and prostate cancer
  • Androgens and AR
  • Epidemiology
  • Progression model
  • Molecular events
  • Prevention
  • Prostate cancer screening and diagnosis
  • Treatment
  • Localized prostate cancer
  • Prognostication
  • Metastatic prostate cancer
  • Disease states model
  • Pre/post hormonal therapy
  • Is AR still a target after castration?
  • Moving beyond hormones to target AR and prostate
    cancer

3
Background
4
Urinary bladder
Prostate
Rectum
Rectal surface
5
Schematic depiction of the cell types within a
human prostatic duct
Androgen Receptor -
Androgen Receptor
Abate-Shen C., Shen M. M. Genes Dev.
2000142410-2434
6
Prostate An androgen-responsive organ
  • Prostate develops after puberty due to production
    of testosterone and more active metabolite
    dihydrotestosterone, which activate AR, the
    androgen receptor
  • AR is a transcription factor which binds to
    consensus sequences and turns on target genes
    such as PSA
  • Prostate contributes to fertility by producing
    enzymes which aid in fertilization of egg
  • Testosterone depletion can prevent prostate
    formation and cancer
  • Eunuchs do not develop prostates and hence do not
    get prostate cancer
  • Testosterone administration has not been found to
    cause prostate cancer in epidemiological studies
    or animals models
  • May raise ones PSA level though and prompt a
    diagnostic work-up

7
AR
Active HSP90
HDAC6
Ac
HDAC6
Ac
Alpha-tubulin
AR
ERG, PSA, and other AR target genes
8
Prostate Cancer Public Health Impact/Demographics
  • Prostate cancer is the most common cancer in men
  • 187,000 new cases estimated for 2008
  • 50,000 recurrences despite early detection and
    treatment
  • Prostate cancer is also the second most lethal
    cancer
  • 27,050 deaths estimated for 2008
  • Previously rare in men lt50
  • 1/5 men will be diagnosed in their lifetime

9
Race and prostate cancer
  • African-Americans are at increased risk of
    prostate cancer development and have more
    aggressive disease
  • Even when one accounts for screening and
    treatment
  • Unknown why
  • Extremely rare in Asian populations
  • Until they move to the U.S.

10
Diet and Prostate Cancer
  • High consumption of broccoli is associated with
    lower prostate cancer risk
  • Kristal, Kolonel, Giavanucci
  • Why?
  • High consumption of red meat particularly charred
    red meat is associated with increased risk
  • PhIP adducts
  • Asians who move to US are at increased risk
  • Diet?

11
Viruses and prostate cancer
  • Men with mutations in an anti-viral gene called
    RNase L more likely to
  • have this virus cDNA present in their cancer
    tissue
  • No causal link demonstrated yet

12
Nelson, et al NEJM 2003
13
Different roads to gene silencing
Genetic - Epigenetic
-
heritable control of gene expression in the
absence of DNA sequence changes
  • DNA methylation
  • Histone methylation

Herman and Baylin NEJM 2003
14
Increase in ERG
Increase in EZH2
Increase in LSD1
Increase in Sonic hedgehog signaling
Nelson, et al NEJM 2003
15
ERG and Prostate Cancer
  • Recent information suggests that ERG is commonly
    up-regulated in prostate cancer
  • This gene is expressed because it is linked to
    TMPRSS2, which AR turns on
  • ERG over-expression leads to enhanced invasion
    and increases one risk of cancer recurrence
  • The VCaP prostate cancer cell line harbors this
    translocation

Science 2005
16
Transgenic ERG mice develop PIN (prostate cancer
precursor lesions)
Benign PIN
Klezovitch , et al PNAS 2008
17
NEJM 2008
18
Prevention
19
  • Inhibits 5-alpha-reductase enzyme which converts
  • testosterone to more active dihydrotestosterone
    agonist of AR protein
  • -Leads to loss of AR function
  • Similar results presented last week at AUA
    meeting for related drug
  • dutasteride

20
Cumulative Incidence of Prostate Cancer Diagnosed
in a Biopsy Performed for Cause or after an
Interim Procedure
Need to treat 16 men to prevent 1 cancer
21
Screening/Diagnosis
22
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23
Prostate cancer screening
  • PSA is very sensitive and easy to do
  • Widely adopted in 1989
  • Led to surge in new diagnoses
  • However,
  • Many men will be diagnosed with
    non-life-threatening cancers with which (rather
    than of which) they might have died
  • Evidence for improvement in survival with
    treatment is modest NNT20
  • Bill-Axelson, et al NEJM 2005
  • May be leading to lead-time bias
  • No high quality RCT has shown a survival benefit

24
Critical appraisal of screening tests
  • Does it do more harm than good?
  • Specific ?s to ask
  • Is there an RCT that early diagnosis leads to
    improved survival and/or QOL?
  • Are the early diagnosed patients willing partners
    in the treatment?
  • How do benefits/harms compare in
    screened/unscreened?
  • Do the frequency and severity of the target
    disorder warrant the degree of effort and
    expenditure?

25
(No Transcript)
26
Number of Diagnoses of All Prostate Cancers
(Panel A) and Number of Prostate-Cancer Deaths
(Panel B)
  • What might explain a negative result in this
    randomized study of screening?
  • 50 of the control arm underwent screening

27
Cumulative Risk of Death from Prostate
Cancer Median F/U 9 years
Never seen a curve like this
Schroder F et al. N Engl J Med 200910.1056/NEJMoa
0810084
28
Take homes for screening
  • Does it do more harm than good?
  • Personal matter
  • Specific ?s to ask
  • Is there an RCT that early diagnosis leads to
    improved survival and/or QOL?
  • Yes improved DSS in ERSPC NNT48 No improved
    DSS in PLCO
  • F/U short
  • Are the early diagnosed patients willing partners
    in the treatment?
  • Yes
  • How do benefits/harms compare in
    screened/unscreened?
  • Unscreened do not have up-front and persistent
    harms of screening/treatment liked screened do
  • Screened have a marginal reduced risk of death in
    ERSPC
  • ? effect on QOL r/e development of symptomatic
    metastases
  • Do the frequency and severity of the target
    disorder warrant the degree of effort and
    expenditure?
  • Very personal decision
  • Presently, we do not have a screening test for
    aggressive prostate cancers

29
Diagnosis
30
Prostate gland
Rectum
31
Definitions
  • Grade How well differentiated a tumor is
  • How closely tumor histologically resembles
    non-tumor/ normal cells of that organ
  • Low-grade Close resemblance
  • High- grade Little resemblance

32
Gleason grading prostate cancer
Assign a number to the primary/ predominant
pattern.
Assign a 2nd number to the secondary pattern.
The sum of the numbers is the Gleason grade/score.
Donald G. Gleason (VAMC) 1977
33
Gleason grading of prostate cancer
Higher grade,worse prognosis
grade 7 (34)
grade 10 (55)
Donald G. Gleason (VAMC) 1977
34
Grade ( how closely prostate cancer cells
resemble normal prostate glands microscopically)
Pattern 3 Gleason grade 336
Pattern 4 Gleason grade 448
Pattern 5 Gleason grade 5510
35
True, et al PNAS 2006
36
Stage Where the tumor is at time of
diagnosis Localized Tumor is confined to the
organ of origin Regional spread Tumor has
invaded adjacent organs Metastatic
Discontiguous spread of tumor to other tissues
T . N . M
T1A, T1B, T1C
Incidental (TUR/PSA)
T2A, T2B , T2C
Localized
T3A, T3B , T3C and T4
Locally-advanced
N(0) vs N() M(0) vs M()
Metastatic
37
Take home points
  • All men have prostate cancer
  • The histology (grade) of a prostate cancer is a
    basis for selecting the type of treatment
  • Molecular determinants of grade are specific
    biomarkers and targets for therapy

38
Prostate cancer treatment
39
Treatment for localized prostate cancer
  • Institutional bias determines which modality is
    given
  • Radical prostatectomy
  • External beam radiation
  • Equal cure rates for early disease
  • No randomized, head-head data comparing these
    approaches
  • Brachytherapy
  • Most well-studied in low risk tumors
  • Androgen-deprivation therapy
  • Patients who are not candidates for surgery or
    radiation
  • Observation
  • Patients with very limited life expectancy due to
    co-morbid conditions
  • Patients with very favorable-appearing tumors

40
Treatment Outcomes in Prostate Cancer
  • Overall survival (OS)
  • Relapse-free survival (RFS)
  • PSA blood test is used to monitor relapse
  • No elevation in PSA or overt disease recurrence

41
Radical prostatectomy
  • Involves removal of the prostate, adjacent
    seminal vesicles, and regional lymph nodes
  • Can be performed as an open procedure or
    laparoscopically /- robotic assistance
  • No head to data comparing the approaches
  • Allows for determination of the pathological
    extent of disease
  • Prognostic
  • May be therapeutic
  • Lymph node removal

42
(No Transcript)
43
Radical Prostatectomy Side Effects
  • Incontinence
  • Impotence
  • Common post-op but improves with time
  • Contrasts with XRT which is less frequent
    immediately post-treatment but increases with
    time
  • More common in older patients and those with
    erectile dysfunction pre-op

44
External Beam Radiation
  • Patients are divided into risk groups based upon
    historical outcomes with XRT
  • clinical stage PSA Gleason
    score
  • Low risk T1c-T2a lt10 6
  • Int risk T2b 10-20 7
  • High risk gtT3 gt20 8-10

-- DAmico (1998) JAMA 280969
45
External Beam Radiation
  • Low risk patients
  • XRT alone
  • Intermediate risk patients
  • Neoadjuvant Hormonal Therapy-gtXRT Concomitant
    Hormonal therapy
  • LHRH-agonist an anti-androgen
  • High risk patients
  • Neoadjuvant Hormonal Therapy-gt XRT Concomitant
    Hormonal Therapy-gtAdjuvant for a total of 3 years
  • LHRH-agonist an anti-androgen
  • Bolla, et al ASCO 2007

46
External Beam Radiation Side Effects
  • Acute
  • Irritative symptoms (rectum and bladder)
  • during treatment and afterwards
  • Chronic
  • Impotence
  • Lower frequency post-treatment than surgery but
    increases over time
  • More responsive to PDE inhibitors than
    post-surgical impotence
  • Irritative symptoms (rectum and bladder)
  • Risk of secondary malignancies

47
Brachytherapy (radioactive seed implantation)
  • Reserved for patients with Gleason scores lt7 with
    clinical stage lt T2b (tumors on only 1 side of
    the prostate) and PSA lt10
  • Follow-up data less mature
  • Side effects
  • Acute
  • Irritative symptoms (urinary)
  • Urinary retention
  • Chronic
  • Impotence
  • Irritative symptoms (rectal and urinary)
  • Fistulas
  • Bleeding

48
Prognostic pathologic parameters(classic)
Prognosis Likelihood of the disease recurring
after x years
  • Serum PSA
  • Stage
  • Grade

49
Kattan nomograms
  • Useful tool to examine outcome for similar
    patients to ones own using wither pre-operative
    or post-operative data
  • Developed from a retrospective database that was
    externally validated
  • Kattan

50
Multivariable Analysis of the Risk of Biochemical
Recurrence N151
Covariate Odds ratio 95 CI P value
Preoperative PSA 1.00 0.91 1.09 0.99
Postoperative Gleason score 3.77 1.87 7.62 0.0002
Extra capsular penetration 4.92 1.31 18.52 0.02
Lymph node involvement 7.26 0.92 57.59 0.06
Seminal vesicle involvement 13.41 1.76 101.84 0.01
Surgical margin involvement 7.73 1.90 31.46 0.004
CDKN2A methylation 0.43 0.10 1.90 0.27
GSTP1 methylation 0.30 0.07 1.24 0.10
ASC methylation 2.08 0.57 7.60 0.27
CDH13 methylation 5.51 1.34 22.67 0.02
RUNX3 methylation 0.60 0.16 2.28 0.45
MGMT methylation 0.33 0.07 1.63 0.17
Preoperative PSA and postoperative Gleason
score were treated as continuous variables CI
Confidence interval
Alumkal, et al 2008
51
Disease States Model of Prostate Cancer
Metastatic Hormone-naive
Metastatic Castrate
Metastatic Castrate Docetaxel-resistant
PSA Relapse Hormone-naive
PSA Relapse Castrate
Localized
Death
52
Metastatic Disease
53
What is happening in the tumor in a metastasis
  • We do not fully know
  • Clinical trials at OHSU
  • Bone biopsy prior to starting therapy to examine
    tumors with microarrays
  • Stratify to specific treatment based upon genes
  • Correlate with response/resistance to treatment
  • Allow for better identification of genes
    responsible for sensitivity/resistance to
    treatments

54
Treating metastases
  • Goals are relief of symptoms and prolongation of
    survival
  • Pain-control is crucial
  • Using most effective and least toxic treatments
    up-front
  • Sequencing treatments

55
Alkaline phosphatase
Prostatic acid phosphatase
56
AR and Androgens in Prostate Cancer
Mutated AR
AR
AR
Testosterone(T)/ Dihydrotestosterone (DHT)
Lower but not absent T/DHT
ARE PSA
ARE PSA
Castrate-resistant (no longer called androgen
independent)
Pre-castrate
57
Hormonal therapy is our most effective treatment
  • LHRH-agonists
  • Over stimulate hypothalamus -gt decreased LHRH-gt
    decreased LH-gt decreased testosterone
  • Initially, these treatments increase testosterone
  • 80-90 PSA response rate
  • Most patients also have objective RRs
  • Median duration response 18-24 months
  • Anti-androgens
  • Compete with testosterone, DHT for binding to AR
  • 30-40 PSA response rate
  • Median duration response 6-12 months
  • Anti-androgen withdrawal response
  • 25 of men progressing on an anti-androgen will
    have a PSA response and palliation of systems for
    4-6 months when anti-androgen is D/Cd
  • Felt to be due to AR mutations, which cause these
    drugs to act as agonists
  • Ketoconazole
  • Inhibits both gonadal and adrenal steroidogenesis
  • 20 RR
  • Median duration response 6-8 months

58
LHRH agonists, DES
Orchiectomy
59
Targeting the Androgen Receptor (AR) Protein
  • AR is the engine of prostate cancer
  • Activated by testosterone, the fuel of prostate
    cancer
  • PSA is a gene which goes up when the engine is on
  • ERG is a gene which can promote prostate cancer
    development and invasion, which goes up when the
    engine is on
  • The wheels of prostate cancer
  • Hormonal treatments inhibit prostate cancer
    mainly by reducing levels of testosterone (fuel)
  • Prostate cancer cells can eventually grow despite
    low levels of testosterone (fuel)
  • We then try to dilute out the remaining fuel with
    water, drugs called anti-androgens

60
Hormonal Treatments
Death of some cancer cells
X
Growth and spread despite low levels of
testosterone (fuel)
Water down the gas further
61
Chemotherapy
62
Supportive Care
  • Bone health
  • Adequate calcium and Vit D to prevent
    osteoporosis from hormonal treatments
  • Bisphosphonates
  • Inhibit osteoclast function
  • When given to men who have castrate-resistant
    metastatic cancers, this helps prevent fractures
  • Pain control
  • XRT
  • Analgesics

63
Is AR still a target when hormonal therapy fails
androgen independence versus castration
resistance?
64
Nature Medicine 2004
65
Cancer Research 2007
66
New therapies targeting AR after castration
resistance appear active
  • MDV3100
  • Abiraterone acetate
  • Reduces adrenal steroidogenesis

Tran, et al Science 2009
67
Looking beyond hormonal therapy to target AR and
prostate cancer our approach
68
Diet, sulforaphane, and prostate cancer
  • There is strong epidemiological evidence for an
    inverse risk of prostate cancer development and
    high intake of cruciferous vegetables, namely
    broccoli
  • Cohen, et al 2000, Kolonel, et al 2000,
    Giovannucci, et al 2003
  • Nonetheless, many people do not consume these
    foods frequently
  • Sulforaphane
  • Broccoli constituent
  • Prevents/delays tumor formation in murine models
    of colon cancer, other tumors
  • Fahey, et al 1997, Chung, et al 2000, Shen, et al
    2007
  • Causes cancer cell death or tumor regression in
    vitro and in prostate cancer xenografts
  • Mechanisms?
  • Induction of Phase 2 detoxification enzymes,
    apoptosis, cell cycle arrest
  • Zhang 2004
  • Histone deacetylase inhibition
  • Myzak, et al 2004

69
SIGNALING
HATs
HDACs
AC
N - K - C
Histone proteins
Non-histone proteins (HSP90, Tubulin)
Chromatin remodeling
Stability (AR, Her2Neu, Bcr-Abl, etc)
Gene expression
slide courtesy of David Qian
70
Centrality of AR in prostate cancer
  • Expressed in nearly all human prostate cancers
  • Key target for prevention and therapy
  • Finasteride, LHRH-agonists, anti-androgens, lyase
    inhibitors, etc
  • Resistance to these therapies is common
  • AR mutations
  • Intratumoral androgens persist despite effective
    serum castration (Mostaghel, et al 2007)
  • Depletion of AR protein is a way to overcome
    these modes of resistance
  • Certain pharmacological HDAC inhibitors lower AR
    protein levels through HDAC6 inhibition and loss
    of HSP90 function
  • Bali, et al 2005, Scroggins, et al 2007
  • Hypothesis
  • We hypothesized that sulforaphane treatment would
    lead to hyperacetylation of HSP90 and that this
    would destabilize AR protein and attenuate AR
    signaling.
  • i.e. We hypothesized we could take out the engine
    block!

71
Gibbs, et al PNAS in revision
72
Taking out the whole engine block (and the
wheels) rather than just the fuel
Gibbs, et al PNAS in revision
73
Gibbs, et al PNAS in revision
74
Sulforaphane
Acetyl
Inactive or reduced levels of HDAC6
X
Decreased de-acetylation of HSP90 and
alpha-tubulin
AR
Hyperacetylated, inactive HSP90
Active HSP90
HDAC6
X
X
X
HDAC6
X
AR
HDAC6
Protein instability and proteasomal degradation
of AR and HDAC6
Inactive or reduced levels of HDAC6
Alpha-tubulin
X
Hyperacetylated alpha-tubulin- ? role
AR
ERG and other AR target genes
ERG and other AR target genes
Gibbs, et al PNAS in revision
75
What we know/dont know
  • ERG over-expression leads to PIN precursor
    lesions in transgenic mice and cellular
    invasiveness
  • 35 of human PIN lesions express ERG
  • Most prostate cancers express ERG
  • Diets high in broccoli are associated with a
    reduced risk of prostate cancer
  • Sulforaphane, in broccoli, shuts down AR and ERG
    (and other AR target genes like PSA) expression
  • Will this prevent prostate cancer precursor
    lesions through this mechanism?
  • Will this lower PSA levels and have anti-cancer
    properties in men with recurrent prostate cancer?

76
To determine whether SFN supplementation in a
murine PIN model of prostate cancer leads to
disruption of AR and ERG expression and reduced
incidence of PIN formation.
X?
ERG
Benign PIN (Prostate cancer
precursor)
SFN
Klezovitch PNAS 2008
77
Current Directions with Sulforaphane
  • Further explore the effect of sulforaphane on
  • prostate cancer cells
  • Feeding ERG transgenic mice sulforaphane to
  • see if we can prevent prostate cancer
  • Clinical trial with sulforaphane in men
  • whose cancers recur despite aggressive
  • treatments like surgery or radiation

78
Specific gene regulation requires the assembly
and coordinate action of demethylases with
distinct substrate specificities
Non-castrate
ON
PSA
LSD1
AR
JHDM2A
Other chromatin modification factors??
JMJD2C
Castrate State
REDUCED (NOT OFF)
PSA
LSD1
AR
JMJD2C
Other chromatin modification factors??
Metzger, et al Nature 2005 Yamane, et al Cell
2006 Wissman, et al Nature Cell Bio 2007
79
LSD1
  • LSD1 (Lysine specific demethylase 1)
  • A monoamine oxidase
  • Silences genes with HDACs, which are commonly
    up-regulated in prostate cancer
  • Shi, et al 2004
  • Found to complex with AR protein and turn on AR
    target genes
  • Metzger, et al 2005
  • Yamane, et al 2006
  • Higher LSD1 levels or low levels of the histone
    mark it removes are associated with prostate
    cancer recurrence
  • Kahl, et al 2006
  • Seligson, et al 2006
  • Inhibition or knock-down of LSD1 leads to reduced
    cell growth
  • Which LSD1 gene targets mediate this??

Turns off genes Turns on genes
Wysocka, et al 2005
80
Treatment with a LSD1 small molecule inhibitor
reduces PSA
ChIP PCR of PSA gene
QRTPCR of PSA gene
81
Check human prostate cancer samples to determine
genes whose expression is directly/inversely
correlated with LSD1 by expression arrays
Vehicle LSD1 inhibitor siNTC siLSD1
Expression arrays after siLSD1 and
pharmacological inhibitor treatment in vitro -293
common genes increase -51 common genes decrease
Check LSD1 ChIP-Chip datasets for genes with
LSD1 enrichment
Putative direct, functional LSD1 targets -Assess
LSD1 occupancy, control of expression -Assess
gene role in transformation
Modified from Yu, et al 2007
82
Summary
  • Prostate cancer is common, detectable, sometimes
    lethal
  • Targeting AR may prevent cancer
  • Diet?
  • Screening can ID cancers
  • Need better methods to screen for aggressive
    cancers
  • Variety of treatment options for localized
    disease
  • Path features and molecular basis for these
    features may aid in prognostication
  • AR is a key target for treatment in all phases of
    the disease (even after castration resistance)
  • Translational, molecular studies hold promise for
    improving patient outcomes

83
Acknowledgements
  • Alumkal lab
  • Angela Gibbs
  • Jacob Schwartzman
  • Dylan Zodrow
  • Lina Gao, PhD
  • Looking for another good
  • post-doc!
  • Fred Hutchinson
  • Larry True
  • Johns Hopkins
  • James Herman
  • Robert Casero
  • Wayne State
  • Pat Wooster
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