Mariano Barbacid-El cáncer como consecuencia del envejecimiento

MOLECULAR ONCOLOGY, CANCER GENOMES MOLECULAR ONCOLOGY, CANCER GENOMES AND PRECISION MEDICINEAND PRECISION MEDICINE

MARIANO MARIANO BARBACID BARBACID CENTRO NACIONAL DE INVESTIGACIONES CENTRO NACIONAL DE INVESTIGACIONES ONCOLÓGICASONCOLÓGICAS

Main developments in Oncology since the turn of the Main developments in Oncology since the turn of the CenturyCentury #1: Targeted Therapies. Almost of the new drugs approved since

1997 are selective inhibitors of molecular targets implicated, more or less directly in cancer development (Targeted Therapies).

In spite of these advances, many tumors still have to be treated with the classical cytotoxic drugs (old chemotherapy regiments) due to the limited number of selective targeted drugs.

Introduction: Key Developments in OncologyIntroduction: Key Developments in Oncology

Novel Drugs in Oncology: FDA ApprovalsNovel Drugs in Oncology: FDA Approvals

Year80 85 90 95 00 05

5

4

3

1New

(no

me

too’

s) D

rugs

Ap

prov

ed b

y th

e FD

A on

a p

er

year

bas

esCytotoxic agentsBiologicalsTargeted drugs

Vaccines

10

2 IF

GlevHer

Ritux

Main developments in Oncology since the turn of the Main developments in Oncology since the turn of the CenturyCentury


#2: Tumor Stratification. The molecular characterization of tumors is allowing scientists to stratify many tumor types into defined subgroups based on either their “driver mutations” or their overall mutational pattern.

This tumor stratification is allowing medical oncologists to treat patients with more selective regiments, hence increasing the overall responses and avoiding unnecessary exposure of the cancer patients to ineffective treatments

Molecular Criteria (driver mutations)

ALK 4%

Adenocarcinoma

Squemous Cell Carcinoma

Tumor StratificationTumor Stratification

Histological Criteria

Lung Lung cancercancer

Small cell lung carcinoma

(20%)Non small cell lung

carcinoma(80%)

Adenocarcinoma

Large cell carcinoma

Squemous carcinoma55% 34%

11%

45%???

K-RAS

22%

EGFR 15%

HER2B-RAF

MAP2K1N-RAS

ROSRET

AKT1PI3K

14%

PI3K 4%

FGFR1 amp

EGFRvIII 5%

DDR2 2%EGFR 2%

65%???

22%

Molecular Criteria

Adenocarcinoma

Squemous Cell Carcinoma

Tumor StratificationTumor Stratification

Histological Criteria

Lung Lung cancercancer

Small cell lung carcinoma

(20%)Non small cell lung

carcinoma(80%)

Adenocarcinoma

Large cell carcinoma

Squemous carcinoma55% 34%

11%

ALK 4%45%???

K-RAS

22%

EGFR 15%

HER2B-RAF

MAP2K1N-RAS

ROSRET

AKT1PI3K

14%

PI3K 4%

FGFR1 amp

EGFRvIII 5%

DDR2 2%EGFR 2%

65%???

22%

Main developments in Oncology since the turn of the Main developments in Oncology since the turn of the CenturyCentury #3: Resistance mechanisms. Targeted therapies have had a

significant beneficial effect in those cancer patients in which they have been used.

However, the effects of these therapies are often short-lived since most patients develop resistance due to secondary mutations in the molecular target or to the activation of alternative pathways


Resistance to Targeted TherapiesResistance to Targeted Therapies

Gleevec and CMLGleevec and CML

EGFR mutant NSCLCEGFR mutant NSCLC


Mutant EGFR +Secondary mutation inT790M

Gefinitib sensitive

Mutant EGFR

Gefitinib resistant

EGFR mutant NSCLCEGFR mutant NSCLC


B-RafB-RafV600E V600E positive metastatic melanomapositive metastatic melanoma


Mechanism of Drug Resistance.

B-RafB-RafV600E V600E positive Metastatic Melanoma treated with positive Metastatic Melanoma treated with Vemurafenib Vemurafenib

Before treatmentBefore treatment After treatmentAfter treatment Resistant to Resistant to VemurafenibVemurafenib


Main developments in Oncology since the turn of the Main developments in Oncology since the turn of the CenturyCentury


#4: Cancer Genomes. The rapid development of ultra-sequencing techniques has allow scientists to routinely sequence cancer genomes. Unfortunately the outcome of these studies has revealed that most tumors contain an unexpected high number of mutations

1.0 mutations por megabase = 3.000 mutations per tumor

Cancer GenomesCancer Genomes

Miscoding mutationsDeletionsAmplifications

Pancreatic Ductal Adenocarcinoma: Exon Pancreatic Ductal Adenocarcinoma: Exon sequencingsequencing




PDACTumors

DNADamage

GTPase Signaling

CellAdhesion

K-Ras Signaling

TGF Signaling

JNKSignaling

Integrin Signaling

Hedgehog Signaling

CellCycle

Apoptosis

Wnt/NotchSignaling

Invasion

DAXX

DEPCD2

PCDH15

K-RAS

SMAD4

ATF2

ITGA4

CREBBP

APC2

TP53

MAP2APG4A

PATIENT 10X

NOS

PRKCG

FAT

K-RAS

BMPR2

NFATC3

LAMA4

BMPR2

CDKN2A

CASP10

TSC2PRSS23



Main developments in Oncology since the turn of the Main developments in Oncology since the turn of the CenturyCentury #5: Tumor Heterogeneity. Deep sequencing of tumor biopsies has

revealed that most solid tumors are not a unique entity, but a group of tumors that have evolved from an initial clone at different times during tumor progression


TejidoNormal

BiopsiesBiopsies Molecular evolution of the tumorMolecular evolution of the tumor

Intra-Tumor Heter0geneityIntra-Tumor Heter0geneity

41 years

13 years

2001

1998

Targeted Therapies: The long road to drug Targeted Therapies: The long road to drug developmentdevelopment

Gleevec

Herceptina

17 years

9 years

4 years

2011

2011

2011

Olaparib

Vemurafenib

Crizotinib

Immunotherapy and CancerImmunotherapy and Cancer

Scientists have always wonder why our immune system is not capable of Scientists have always wonder why our immune system is not capable of recognize and reject our tumorsrecognize and reject our tumors

In fact, for many years they have tried to develop antibodies against “tumor In fact, for many years they have tried to develop antibodies against “tumor antigens”antigens”

Unfortunatey, tumor plasticity allows tumors to evolve tumor variants that no Unfortunatey, tumor plasticity allows tumors to evolve tumor variants that no longer express such “tumor antigenes” since these antigen are not essential longer express such “tumor antigenes” since these antigen are not essential for tumor maintenancefor tumor maintenance

In the 90s some scientists decide to potentiate the adaptive response by In the 90s some scientists decide to potentiate the adaptive response by stimulating the cytotoxic T lymphocytes using IL-2 as well as other stimulating the cytotoxic T lymphocytes using IL-2 as well as other cytokinnes.cytokinnes.

Unfortunatley, this approach, although obtained a few responses specially in Unfortunatley, this approach, although obtained a few responses specially in young people, had to be abandoned due to its high toxicity since the over-young people, had to be abandoned due to its high toxicity since the over-activated T lymphocytes also attacked our nomral tissues.activated T lymphocytes also attacked our nomral tissues.

During the last few years, scientists appear to have discover a way t During the last few years, scientists appear to have discover a way t manipulate our immune system to fight, at least certain cancers, mainly manipulate our immune system to fight, at least certain cancers, mainly matastatic melanoma.matastatic melanoma.The key discovery has been, not to stimulate our immune systme, but The key discovery has been, not to stimulate our immune systme, but to to inhibit its desactivationinhibit its desactivation

Our organism is able to mount an immune response to defend us from Our organism is able to mount an immune response to defend us from infections by potentiating the infections by potentiating the innateinnate (mainly (mainly dendritic cells, NK cells, macrophages, neutrophils, etc.) and the and the adaptiveadaptive (B and T lymphocytes) (B and T lymphocytes) responses. Yet, at the same time, our organisms has developed responses. Yet, at the same time, our organisms has developed sophysticated mechanisms to dampen this response once the infection has sophysticated mechanisms to dampen this response once the infection has subsided. subsided.

Thus, some scientists decided to block those proteins implicated in Thus, some scientists decided to block those proteins implicated in deactivation of the cytotoxic T lymphocytes, mainly CTLA-4 and PD1, now deactivation of the cytotoxic T lymphocytes, mainly CTLA-4 and PD1, now part of a complex regulatory mechanism known as the “part of a complex regulatory mechanism known as the “immune immune checkpointscheckpoints”. ”. In other words, the “solution” has been to “inhibit the inbitors”In other words, the “solution” has been to “inhibit the inbitors”

Indeed, without these inhibitory mechanims we may end up developong Indeed, without these inhibitory mechanims we may end up developong auto-immune or immunedegenerative diseases. auto-immune or immunedegenerative diseases.


Based on these studies, several pharmaceutical companies have developed Based on these studies, several pharmaceutical companies have developed monoclonal antibodies against these immune checkpoints.monoclonal antibodies against these immune checkpoints.

The first inhibitors to be approved by the FDA are Ipilimumab (2011), a MAb The first inhibitors to be approved by the FDA are Ipilimumab (2011), a MAb against CTLA-4 and Pembrolizumab (2014) a MAb against PD-1against CTLA-4 and Pembrolizumab (2014) a MAb against PD-1

The T lymphocytes are activated by the interaction

of B7 with CD28

Activated T Activated T lymphocytelymphocyte

To deactivate, they express a molecule,

CTLA4, that competes with Cd28 for B7

Inactive T lymphocyteInactive T lymphocyte

If CTLA4 is blocked by a MAb, the T cells remain

active

Active T lymphocyteActive T lymphocyte


Metastatic Metastatic MelanomaMelanoma

Tum

or re

spon

se (%

)Tu

mor

resp

onse

(%)

Patients treated with Pembrolizumab (anti-PD1)Patients treated with Pembrolizumab (anti-PD1)


Pacie

ntes

sin

prog

resio

n tu

mor

al (%

)Pa

cient

es si

n pr

ogre

sion

tum

oral

(%) Squamous NSCLC (Brahmer et al., NEJM, May 2015)Squamous NSCLC (Brahmer et al., NEJM, May 2015)


Non-Squamous NSCLC (Borghaei et al., NEJM, Sept 2015)Non-Squamous NSCLC (Borghaei et al., NEJM, Sept 2015)


These results have been generated based on just two immune checkpoints These results have been generated based on just two immune checkpoints that regulate the immune response elicited by T cells, CTLA4/B7.1 and that regulate the immune response elicited by T cells, CTLA4/B7.1 and PD1/PDL1 PD1/PDL1


Since there are many other immune checkpoints it is quite possible that Since there are many other immune checkpoints it is quite possible that immunotherapy might expand its use to the treatment of many other types of immunotherapy might expand its use to the treatment of many other types of cancercancer


Introduction: Basic Concepts in OncologyIntroduction: Basic Concepts in Oncology

Cancer IS NOT a single disease.

Now that we can sequence the cancer genomes, we can say with a significant degree of confidence that, in the same way there are no two identical individuals, there are no two identical tumors

The term “cancer” encompasses more than 200 different diseases depending on (i) the organ and (ii) the cell type in which it originates, as well as on (iii) its mutational content and (iv) its epigenetic profile

Incidence vs. MortalityIncidence vs. Mortality

IncidenceIncidence

Tipos de cáncer: Incidencia vs. Tipos de cáncer: Incidencia vs. MortalidadMortalidadMortalityMortality

All these advances in our understanding of cancer as a complex group of diseases and in the development of better treatments have been possible thanks ot the combined efforts of hundreds of basic and clinical scientists as well as to Governments that unlike ours, understand the need for continuous support of cancer research.

A COUNTRY WITHOUT RESEARCH, IS A COUNTRY WITHOUT FUTURE!!

Mariano Barbacid-El cáncer como consecuencia del envejecimiento

Health & Medicine

Transcript of Mariano Barbacid-El cáncer como consecuencia del envejecimiento