Cancer Treatment: The Challenge

1
GEORGE MASON - INOVA HEALTH SYSTEMS
TRANSLATIONAL RESEARCH CENTERS

A NEW PARADIGM FOR APPLIED MOLECULAR MEDICINE
2

• George Mason University-Inova Health System
  Translational Research Center

• Clinical Focus
• Cancer
• Metabolic syndromes/obesity
• Cardiopulmonary diseases
• Neurodegenerative disorders
• Liver diseases.

GOAL To accelerate cutting-edge research
discoveries for patient-tailored
research and personalized medicine at the
bedside. Daniele Struppa

• A joint initiative, under a unique partnership
  between a public university and
• a large community hospital system to coordinate
  multiple programs for a
• systems biology approach to Molecular Medicine
• Proteomics
• Nanotechnology
• Biomedical Genomics

3
DNA The blueprints

• PROTEINS The Working Machinery

4
Proteomics The next revolution in medicine
The GMU Center for Applied Proteomics and
Molecular Medicine Lance Liotta and Emanuel
Petricoin Co-Directors

• New blood tests for early disease diagnosis
• Individualized new therapy tailored to the
  patient and their disease
• Reduced side effects from therapy

5
Proteomics Example Applications Beyond Cancer

• Cardiovascular Disease
• Imaging of occluded heart arteries
• Blockade of thrombus formation the main cause of
  heart attacks

• Diabetes and Obesity
• Individualized metabolic profiling for diet and
  lifestyle management
• Improve survival of pancreatic islet
  transplants hope for a cure

• Individualized Adult Stem Cell Therapy
• Harvest adult stem cells from bone marrow or fat
  tissue stimulate them to repair the diseased
  tissue administer the stimulated cells back to
  the patient who donated them.

6
IF WE CAN FIRST FIND OUT WHICH PATIENT SHOULD
GET WHICH TARGETED MEDICINE
7
Cancer Treatment The Challenge
The Outcome
8
Cancer Treatment Individualized Therapy
A group of patients all have lung cancer
9
Patient
Biopsy
Microdissection
Protein microarray State of phosphorylated cell
signaling proteins
10
LASER CAPTURE MICRODISSECTION
11
Childhood Rhabdomyosarcoma

• 70 of all rhabdomyosarcoma cases are diagnosed
  in the first ten years of life. It is frequently
  metastatic at diagnosis.
• Despite advances in chemotherapy, 40 of the
  children no not respond to standard treatment.

Why do some patients fail therapy? What is
different about their cancer? Can we change a
non-responder into a successful treatment?
Successful Treatment
12
(No Transcript)
13
Low AKTser473
Low 4EBP1Thr37
AKT ser473 plt0.0001
High 4EBP1Thr37
High AKTser473
4EBP1Thr37/46 plt0.0110
AKT ser473 plt0.0009
4EBP1Thr37/46 plt0.0106
14
CCI 779 DRUG CANDIDATE FOR MTOR PATHWAY
INHIBITION CCI-779 inhibitions of tumor growth in
RMS xenografts
Hypothesis Pulse treatment with an mTOR
inhibitor prior to chemotherapy will convert a
non-responder rhabdomyosarcoma into a therapy
success.
A
B
Rh30-xenograft
vehicle
CCI-779
CCI-779
M T M T M T
p-S6 (S235/236)
Tumor volume (mm3)
Actin
p-4E-BP1(T70)
RD-xenograft
vehicle
CCI-779
CCI-779
M T M T M T
p-S6 (S235/236)
Actin
p-4E-BP1(T70)
CCI-779 inhibiter tumor growth in Rh30 and RD
xenografts. Cells (2 x 106) in 0.2 ml per mouse
were injected orthotopically into the
gastronemius muscle in the left hind leg, and
after 1 week mice were assigned to control or
CCI-779 treatment. CCI-779 was given at 20
mg/kg/IP every 3 days for 30 days (A). Protein
extracts from Rh30 and RD tumors treated with
CCI-779 or vehicle for 30 days and were analyzed
by Western blotting for S6 and 4E-BP1
phosphorylation (B).
15
Ovarian Cancer is diagnosed when it is too late
16
Early Detection of Lung Cancer
Leading cause of cancer death in the USA. Most
lung cancer is diagnosed at a very late stage
Only 5 live 5 years.
17
Written in Blood Circulating proteins offer an
ongoing recording of health and disease in every
organ of the body
Molecular Mop Collects Circulating Protein
Disease Markers for Later Harvest
18
A NEW PARADIGM
Map Circuitry
Serum Proteomics Early Diagnosis
Biopsy
Diagnostic Imaging
Administer Individualized Therapy
19
Adopt a PatientAdopt a Clinical Research Trial

• Individualized Therapy For Lung Cancer
• New Hope Individualized Therapy for all types
  of metastatic solid tumors
• Diagnostic blood tests for early stage breast,
  ovarian and lung cancers

20
Low eIF4G ser1108
Low p70S6 Thr389
High p70S6 Thr389
High eIF4G ser1108
eIF4G ser1108 plt0.0017
p70S6 Thr389 plt0.0085
eIF4G ser1108 plt0.0072
p70S6 Thr389 plt0.0296
21
Personalized Molecular Medicine
EARLY DETECTION BY SERUM PROTEOMICS AND MOLECUAR
IMAGING

• CANCER DETECTION WHEN IT IS TOO LATE

MOLECULAR PROFILING OF TISSUE CELLS

• PATHOLOGIC DIAGNOSIS BASED ON HISTOLOGY

COMBINATION THERAPY TAILORED TO INDIVIDUAL
PATIENTS MOLECULAR PROFILE

• THERAPY CHOICE BY CATEGORY OF DISEASE

MULTIPLE TARGETS ALONG THE LENGTH OF KEY SIGNAL
TRANSDUCTION PATHWAYS INTRACELLULAR AND
EXTRACELLULAR

• SINGLE TARGETS SINGLE THERAPEUTIC AGENTS

DIRECT MONITORING OF CELLULAR TARGETS BEFORE,
DURING, AND AFTER THERAPY REAL TIME EFFICACY,
AND TOXICITY

• EFFICACY DETERMINED BY WAITING FOR RESPONSE OR
  RECURRENCE

22
The next revolution Molecular Profiling
Individualized Therapy
Signal Network Profile
Gene Microarray
Patient
EGFR signature, 452 genes in 74 cases
Biopsy
Choose combination therapy tailored to pathogenic
defect
Rational basis for revising therapy following
recurrence
Monitor success of therapy
EGFR Pathway
Protein Microarray
Microdissection
Phosphorylated states of signal pathway proteins