Treatment Approaches in Pancreatic Cancer€¦ · 10/11/2013 10 Advanced pancreatic cancer: Systemic treatment options Patientcategory First-line Second-line PS 0-2 and Adequateliver

10/11/2013

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Treatment Approaches in

Pancreatic Cancer

Philip Agop Philip, MD, PhD, FRCP

Professor of Oncology

Leader, GI and Neuroendocrine Multidisciplinary Team

Karmanos Cancer Center

Wayne State University

Detroit

Karmanos Cancer Center

NCI-designated comprehensive cancer

center

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Outline

• Background information

• Current treatment approaches

• The hope of targeted therapies

• Providing comprehensive care

• Concluding remarks

Fighting pancreatic cancer

• Expanding our basic knowledge of the disease

• Applying the new science in the development

of new and effective therapies

• Providing patients with access to clinical trials

using new drugs

• Providing patients a high level

multidisciplinary care

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A Major Challenge

Not diagnosed at an early

stage!

The Pancreas

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Pancreatic cancer

• The vast majority of patients diagnosed with

pancreatic cancer have micro- or overt

metastatic disease

• Improvements in outcome in patients with

pancreatic cancer will depend on developing

better drug (systemic) therapies

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What makes pancreatic cancer

an aggressive cancer?

• The cancer cells can travel to

other parts of the body

• The cancer cells are somewhat

resistant to conventional drug

therapies and radiation

Outline






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Treatment options based on disease

stage

Stage of pancreatic cancer Treatment

Localized and vessels free Radical resection +/-

chemotherapy/radiothe

rapy

Localized but some vessels

involved (borderline)

Chemotherapy followed

by resection

Localized but vessels encased Chemotherapy +/-

radiotherapy

Metastases or spread to

other sites

Chemotherapy

Chemotherapy is needed in almost

every patient with this disease

Stage of pancreatic cancer Treatment

Localized and vessels free Radical resection +/-

chemotherapy/radiothe

rapy

Localized some vessels

involved (borderline)

Chemotherapy followed

by resection

Localized but vessels encased Chemotherapy +/-

radiotherapy

Metastases or spread to

other sites

Chemotherapy

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Almost everyone with pancreatic

cancer needs drug therapy, even

those with early disease

Increasing availability of drugs to

treat pancreatic cancer

Gemcitabine (Gemzar)

Erlotinib (Tarceva)

FOLFIRINOX

2

0

1

0

2

0

0

5

1

9

9

6

Nab-paclitaxel

(Abraxane)

2

0

1

3

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Remissions on FOLFIRINOX

patient #1

Before After

Remissions on FOLFIRINOX

patient #2

Before After

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Side effects to drugs:

Milder treatments

• Gemcitabine (Gemzar)

– Low blood counts

– Fatigue

– Leg swelling

• Erlotinib (Tarceva)

– Skin rash

– Diarrhea

Side effects to drugs:

more intense treatments

• FOLFIRINOX– Nausea with or without vomiting

– Diarrhea

– Fatigue

– Effect on blood counts

– Infection

– Neuropathy

• Gemcitabine/nab-paclitaxel (Abraxane)– Fatigue

– Effects on blood counts

– Nausea with or without vomiting

– Neuropathy

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Advanced pancreatic cancer:

Systemic treatment options

Patient category First-line Second-line

PS 0-2 and

Adequate liver function

including good albumin

• Clinical trial

• mFOLFIRINOX

• Gemcitabine/nab-

paclitaxel

• Gemcitabine +/- erlotinib

• Clinical trial

• Gemcitabine-

based regimen

• mFOLFIRINOX

• mFOLFOX6

• Capecitabine

PS 2-3 and/or

Major liver

dysfunction/poor

albumin


paclitaxel


• Clinical trial

• mFOLFOX6

• Capecitabine

• Clinical trial

• Supportive care

alone

PS 3-4

Major ascites

Recurrent biliary stent

problems

• Gemcitabine, or

• Supportive care alone

Advanced pancreatic cancer:

Systemic treatment options

Patient category First-line Second-line

PS 0-2 and

Adequate liver function

including good albumin

• Clinical trial

• mFOLFIRINOX


paclitaxel


• Clinical trial

• Gemcitabine-

based regimen

• mFOLFIRINOX

• mFOLFOX6

• Capecitabine

PS 2-3 and/or

Major liver

dysfunction/poor

albumin


paclitaxel


• Clinical trial

• mFOLFOX6

• Capecitabine

• Clinical trial

• Supportive care

alone

PS 3-4

Major ascites

Recurrent biliary stent

problems

• Gemcitabine, or

• Supportive care alone

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What are the challenges with the

conventional “chemo”?

• Less specific against cancer cells

(also affects normal cells)

• Side effects

• Cancer cells develop resistance

(immunity) to these drugs

What is needed?

• A better understanding of what causes

resistance to drugs

• Discovery of better drugs that have

specific targets

• Personalizing therapies

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Outline






Era of Targeted Therapies

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Disease behavior dictated by genetic

mutations in the tumor

Complexity of genetic mutations in pancreatic

tumors

• 20,661 genes

• Average 63

alterations per

patient

• Mostly point

mutations

Jones et al, Science, September, 2008

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Cancer Genes:

the “good” and “bad ones”

Bad genes

Oncogenes

Good genes

Tumor suppressor genes

Push the cell to divide,

spread and dodge

treatments

Put the brakes on cell

division and spread

Examples

Her-2, KRAS

Examples

p53, p16

How to target?

• Disrupting a signaling cascade within the

cancer

•

• Cutting off blood supply to tumor

• Regaining the function of the “good” or tumor

suppressor genes

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Harari, P. M. et al. J Clin Oncol; 25:4057-4065 2007

Redundancies and Cross Talks

Redundancies of signaling pathways:

Where to block?

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Drug combinations or cocktails

• Hitting multiple targets in the cancer cell

simultaneously

• Preventing the emergence of drug resistance

• Success in HIV disease and in other cancers

PI3K

Akt

4EBP1

Ras

MEK

Raf

P

ERK

FOXO

PTEN

RTKs

TORC1/TORC2

RSK

S6K

Cross-TalkCross-TalkPDK1

Grb10

Survival, proliferation, metabolism, angiogenesis

MEK downstream of activated RAS

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Randomized Phase II Clinical Trial of AZD6244

(Selumetinib) and MK2206 vs. mFOLFOX in

Patients with Metastatic Pancreatic Cancer after

Prior Chemotherapy

SWOG 1115

Dr. Vincent Chung

City of Hope

Young Investigator

IRS

PI3K

Akt

mTOR

Ras

MEK

Raf1

IGF-1R

EGFR

MEK & Akt dual

“downstream” blockade

P PShc

ERK

MK2066

AZD

MK2206

AZD2264

Proliferation

Drug resistance

AngiogenesisEngleman et al, Nature Medicine 14, 1351 - 1356 (2008)

S1115

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Targeting Nuclear Export Protein

CRM-1 in Pancreatic Cancer using

KPT-330

CRM-1 is the major protein exporter of

tumor suppressor proteins

�Nuclear localization of Tumor Suppressor Proteins (TSPs) is key to their

surveillance activity

� Cancer cells suppress TSP function through their constant export utilizing

CRM-1

� Elevated CRM-1 expression has been correlated with poor prognosis in

different cancers and is considered a driver of chemotherapy resistance

CRM-1

Cancer Cell

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Nuclear Transport Machinery

Attacking the cancer cell is NOT

enough

Must also destroy the

neighborhoods that hide and

support the bad cells!

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Stromal influence on pathogenesis and

progression

Stromal compartment is a new target

Olson and Hananhan, Science, 324:1400-1401, 2009

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Cancer cellStroma

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Hyaluronan (HA) as a target in Pancreatic

Cancer:

• HA overexpression in > 80% of pancreatic

cancers

• Tumors that accumulate HA develop high

interstitial fluid pressure and drug resistance

• HA is associated with disease progression

and poor prognosis

A PHASE IB/II RANDOMIZED STUDY OF MODIFIED FOLFIRINOX +

PEGYLATED RECOMBINANT HUMAN HYALURONIDASE (PEGPH20) VERSUS

MODIFIED FOLFIRINOX ALONE IN PATIENTS WITH GOOD PERFORMANCE

STATUS METASTATIC PANCREATIC ADENOCARCINOMA

S1313

Ramesh Ramanathan

in collaboration with Halozyme

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Targeting the stem cells in the

tumor

Finding and removing the needle in

the haystack

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SCSC

Normal Cancer

Stem cell

SCSC SC

Normal Cancer

Stem cell

Tumor proliferation

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SCSC SCSC

Normal Cancer

Stem cell

Tumor proliferation

Treatment

SCSC SCSC

Normal Cancer

Stem cell

Tumor proliferation

Treatment Failure of treatment

= Relapse

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SCSC SCSC

Normal Cancer

Stem cell

Tumor proliferation

Treatment Failure of treatment

= Relapse

Detect the SC

Before forms tumor

SCSC SC

Normal Cancer

Stem cell

Tumor proliferation

Treatment

CURE!

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Outline






Patients with pancreatic need a

comprehensive multidisciplinary care

• Symptom management

– Pain

– Nutrition

– Depression

• Requirements for multiple forms of therapies

– Drugs or chemo

– Surgery

– Radiation

• Psychosocial support

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Research and Clinical Trials

Research and Clinical Trials

Only 4% of patients are enrolled in

clinical trials in the USA

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A mouse carrying a cancer is not the same

as a patient with cancer

Status of clinical trials in pancreatic

cancer: a PanCan analysis

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Pancreatic cancer clinical trials open in United States in 2011 and

2012 by phase.

Hoos W A et al. JCO 2013;31:3432-3438

Most available clinical trials are in advanced disease

Hoos W A et al. JCO 2013;31:3432-3438

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Most clinical trials are using targted agents

Hoos W A et al. JCO 2013;31:3432-3438

More trials are available in larger cities in the US

Hoos W A et al. JCO 2013;31:3432-3438

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The 133 pancreatic cancer–specific clinical trials open in United States in 2011 were identified by sponsor indicated in clinicaltrials.gov.

Hoos W A et al. JCO 2013;31:3432-3438

Specific research strategies at Karmanos

• To identify why pancreas cancer cells are resistant to therapy

• To develop molecular techniques that would explain the processes for resistance in a given patient

• To design treatments that would overcome drug resistance

• To take advantage of the highly integrated pancreas cancer care delivery system at Karmanos and national research collaborations

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SUMMARY

• Newer drugs starting to improve the outcome of patients with pancreatic cancer

• New treatments are being developed that are based on advances in science

• Patients must be encouraged to participate in clinical trials

• Need for personalized therapies

[email protected]

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Treatment Approaches in Pancreatic Cancer€¦ · 10/11/2013 10 Advanced pancreatic cancer: Systemic treatment options Patientcategory First-line Second-line PS 0-2 and Adequateliver