The Challenge of Prostate Cancer

Genitourinary Cancer Genitourinary Cancer Center at M. D. AndersonCenter at M. D. Anderson

PERSONALIZED MEDICINE

30,000Die of cancer

~ 350,000 patientsdiagnosed

~125,000 needtreatment

Prostate Cancer Dilemma!

30,000Die of cancer

~ 350,000 patientsdiagnosed

~125,000 needtreatment

WE MAY BE OVER DIAGNOSING 150,OOO ANNUALLY !

Androgen-Dependent Prostate CancerAndrogen-Dependent Prostate Cancer

Acquisition of Complementary Genetic LesionsAcquisition of Complementary Genetic Lesions

Clonal ExpansionClonal Expansion

Cancers Adapt to Challenge of Therapy

Adaptation

Hormone Ablation TherapyHormone Ablation Therapy

“Ability to adapt” can be used to distinguish cancer types

Finasteride

Lethal genetic networks

Indolent genetic networks

Surgery

Surveillance

Assessing response to Finasteride will distinguish cancers with lethal potential from those that can be observed & spared complications of therapy

Cancer Cell

Fat Cell

Weight Change age 25 to Dx

Mean Time to Biochemical Failure

(months)

Loss/No Change <0.5kg/yr . . . 40.9

Gain 0.5 - 1.5 kg/yr . . . . . . . . . 25.8

Gain > 1.5 kg/yr . . . . . . . . . . . . 16.7

p=0.003

Reversal of Obesity by Targeted Ablation of Adipose Tissue

Control TreatedControl TreatedKolonin et al, Nature Med., 2004, 10, 625-32

Increased number of fat cells induce prostate cancer aggressiveness & if blocked will retard cancer growth

The Challenge

PSA Relapse (>0.4 ng/ml)

RadiotherapyObservation

100

80

60

40

20

0 80 6040 200

Years From Registration

Per

cent

age

Log-Rank P<.001

No. at Risk

Thompson et alJAMA 11/06

If Prostatectomy were a drug!

Benefited 7%* Incomplete 18%** Unnecessary 40% Futile 35% Total 100%

* By survival** By PSA recurrence

Principles of Therapy(Localized Cancers)

1) Low stage & Low Grade cancers can be monitored for delayed therapy2) Higher Grade Cancers generally require treatment3) Surgery Preferred in younger patients radiation in older4) Higher grade cancers often require combinations (Hormones & Surgery or Radiation)5) Consideration of patient preference often deciding factor given excellent choices

Distinguishing cancer able to invade adjacent tissue from the remainder will allow us to individualize application of therapy

Cancer Cell

Host Cell

Environment a Determinant of Cancer Invasion & is Normally a well choreographed process

The effect of signaling of normal development

1

3

1 1

3

2

1

1

++

+ +

1

-

-

2

1

2

2

-

DOES NOT OCCUR IN MICE!!

Androgen DependentHigh Risk Prostate Cancer

ProstatectomyThalidomide

CT Perfusion Study

Pretreatment Posttreatment

Time

Th

era

py

Eff

ec

t

microenvironment epithelial cell

Serial Modulation Microenvironment & Neoplastic Epithelium

TIME

The

rapy

Eff

ect

Interrupting the "organizational sequence" used by prostate cancer for its growth will result in effective therapy

Modeling Human Prostate Cancer

35 models

Model Prostate Cancer in Bone

Human Prostate Cancer “Produces Bone”

Working Hypothesis

Bone Development Pathways “usurped” by human Prostate cancer and accounts for the

observed phenotype

Blocking Cancer Growth in Bone

(A Priority Therapy Target)

Results 50% of treated mice had very little tumor

Control Treatment

Current Medical Care

Reactive Medicine

Current Medicine

Symptom Diagnosis Treatment

(Reactive)

Medical Care In the information age

(Individualized Therapy)

Understand Anticipate Apply

Toxicology

AnatomyMedical

OncologyBiostats

Pharmacology Pathology

Tumor Biology

Meaningful Knowledge

Radiation

Surgery

Cur

e R

ate

Toxicology

AnatomyMedical

OncologyBiostats

Pharmacology Pathology

Tumor Biology

Meaningful Knowledge

Radiation

Surgery

Cur

e R

ate

Patients

A Team Effort with the Patient at the Center!

Individualized Therapy

Power of Patient Advocacy

Patient advocacy has influenced national health priorities and research direction

Thank You!