Research biopsies and

translational research

protocol participation

Jennifer A. Wargo, MD, MMSc

Departments of

Surgical Oncology & Genomic Medicine

Melanoma Research Foundation

Understanding Melanoma:

From Prevention to Cure

Houston, TX

January 31, 2015

Targeted therapy

Immunotherapy

• Cancer is a disease of the DNA

• Genetic mutations may result in the development of cancer

• These genetic mutations can lead to increased growth and spread of tumors

• Targeting these mutations may allow us to stop the cancer cells from growing and spreading and may kill the tumor cells (BRAF gene)

Targeted Therapy for Melanoma

CRAFBRAF

PI3KMEK

AKT

mTOR

CDK2 CDK4

PTEN

p16CyclinD

60%

c-kit

30% 20%

5%

40%

10%

NRAS

ERK

Melanoma

Oncogenic BRAF in Melanoma

CRAFBRAF

MEK

ERK

BRAF

Uncontrolled

growth

Resistance to

killing

Growing new

blood vessels

Ability to

spread

Ability to escape from

the immune system

Oncogenic BRAF in Melanoma

CRAFBRAF

MEK

ERK

BRAF

Uncontrolled

growth

Resistance to

killing

Growing new

blood vessels

Ability to

spread

Ability to escape from

the immune system

X

BRAF inhibitor

(Vemurafenib,

Dabrafenib)

Treatment with a BRAF inhibitor often results in rapid shrinkage of tumors

Before starting a

BRAF inhibitor 2 weeks later

RECIST 30% Decrease

Most patients who take a BRAF inhibitor will have their tumors shrink

However the tumors often come back within 6 months

Why do tumors respond to treatment

but then grow again?

Patients with

advanced

melanoma

being treated

with a BRAF

inhibitor

Enrolled

onto

research

protocols

Blood draw

and tumor

biopsy

Start of

therapy Blood draw

and tumor

biopsy

Restaging

with CAT

scansBlood draw and

tumor biopsy

If/when tumor

re-grows

Tumors and blood checked for:

• genetic changes and

• immune response

CRAFBRAF

PI3KMEK

AKT

mTOR

CDK2 CDK4

PTEN

p16CyclinD

NRAS

ERK

Multiple genetic changes found in the tumor

which help them re-grow on BRAF inhibitors

BRAFBRAF

BRAF

amplification,

splice variants

NRAS

NRAS

mutations

COT

CRAF

Over-expression of

COT (MEK kinase)

Receptor activation (PDGFRb, IGF1R, cMET, EGFR)

MEK1 mutations

CyclinDOver-expression of

CyclinD

PTENAKT

PTEN loss

leading to

AKT

activation

MEK

Frederick, et al.

Clinical Cancer

Research 2013

Melanoma

protein

recognized by

immune cells

The immune system may help the body destroy

tumors treated with BRAF inhibitors…

Immune cells

attacking the

tumor (TIL)

Tumor making

proteins to shut

down the

immune system

Before BRAF inhibitor BRAF inhibitor – 2 weeks

but tumors may block the immune system again

Targeted therapy

• Though the majority of patients who

get targeted therapy have their tumors

shrink or go away, the effect is not

long lasting in most patients

(most tumors come back in 6 months)

• We are doing studies to understand

why melanomas become “resistant” to

this therapy, and a lot of what we

learned has been through the analysis

of tumor biopsies over time

Immunotherapy

• Though we sometimes see dramatic

responses to immunotherapy, it

doesn’t work in all patients

• We are doing studies to understand

why some people respond and why

others do not, and are learning this by

analyzing tumor biopsies over time

• We are also trying to understand why

tumors sometimes shrink but do not

go away

How can we unlock the mysteries of

response to therapy?

They key to understanding what is

happening in the tumor is to do biopsies

How do we do the biopsies?

How do we do the biopsies?

How do we do the biopsies?

What studies are done on these?

DNA is

isolated and

tested

Results

reported to

help guide

therapy

What studies are done on these?

Immune cells in

the tumor and

blood are

analyzed

Results are being

used in clinical

trials and will help

guide therapy

Can these studies help patients with

melanoma?

They already have!

Research into genetic

changes and immune changes

in tumors have already led to

advances in treatment

CRAFBRAF

MEK

ERK

BRAF

Uncontrolled

growth

Resistance to

killing

Growing new

blood vessels

Ability to

spread

Ability to escape from

the immune system

X

BRAF inhibitor

(Vemurafenib,

Dabrafenib)

MEK

Treatment modified based on genetic

changes identified

CRAFBRAF

MEK

ERK

BRAF

Uncontrolled

growth

Resistance to

killing

Growing new

blood vessels

Ability to

spread

Ability to escape from

the immune system

X

BRAF inhibitor

(Vemurafenib,

Dabrafenib)

MEK

Treatment modified based on genetic

changes identified

MEK inhibitor

(Trametinib,

Cobimetinib)

X

Combinations of a BRAF

inhibitor and a MEK inhibitor

are now being used in the

treatment of advanced

melanoma

Treatment modified based on immune

changes identified

CRAFBRAF

MEK

ERK

BRAFX

BRAF inhibitor

(Vemurafenib,

Dabrafenib)

Ipilumumab,

anti-PD-L1

anti-PD-1

Anti-Tumor T Cell

Combination of BRAF

inhibitors and immunotherapy

are now in clinical trials and

show promise for patients with

advanced melanoma

BRAF inhibitor + Ipilimumab

BRAF inhibitor + PD-L1

BRAF inhibitor + TIL

Cooper et al, Cancer Immunology Research 2014

What can we learn from doing

more biopsies?

CD8

We can learn why treatments are working,

and if not –

what we can do to make them work!

When may my doctor ask me if I am

willing to have a biopsy?

Clinical indications:

• Diagnosis of an abnormal area (from exam

or from CT scans)

• As indicated for a clinical trial (for

enrollment or during treatment)

Research:

•Ultimate goal is to cure ALL patients with

melanoma – research is critical to this

•You can help others beat this disease!

The Melanoma

Moon Shot ProgramThese efforts are going on worldwide

through outstanding research studies

We are all

working together

to cure melanoma

AcknowledgementsMelanoma Research Foundation

Patients, families, participants

Other speakers

Laboratory InvestigationZachary Cooper, PhD

Alexandre Reuben, PhD

Jacob Austin-Breneman, BS

Hong Jiang, MS

Dennie T. Frederick, MS

Devarati Mitra, MD PhD

Vikram Juneja

MGH / Harvard CollaboratorsDavid Fisher, MD PhD

Keith Flaherty, MD

Arlene Sharpe, MD PhD

Lyn Duncan, MD

Adriano Piris, MD

Don Lawrence, MD

Ryan Sullivan, MD

MDACC CollaboratorsPatrick Hwu MD, Mike Davies MD PhD

Roda Amaria MD, other melanoma med onc

Merrick Ross MD, Jeff Gershenwald MD

Jeff Lee MD (other surg onc colleagues)

Many other MDACC past, present, and future

collaborators

Other Mentors / CollaboratorsAntoni Ribas, MD

Steven A. Rosenberg, MD PhD

Philanthropic / Grant SupportK08 and TMEN Grant support

Industry Sponsors for TrialsGenentech, GSK, BMS

Merck, MedImmune

Patients treated on trial (& families)

Questions?