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
Introduction: Key Developments in OncologyIntroduction: Key Developments in Oncology
#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
Introduction: Key Developments in OncologyIntroduction: Key Developments in Oncology
Resistance to Targeted TherapiesResistance to Targeted Therapies
Gleevec and CMLGleevec and CML
EGFR mutant NSCLCEGFR mutant NSCLC
Resistance to Targeted TherapiesResistance to Targeted Therapies
Mutant EGFR +Secondary mutation inT790M
Gefinitib sensitive
Mutant EGFR
Gefitinib resistant
EGFR mutant NSCLCEGFR mutant NSCLC
Resistance to Targeted TherapiesResistance to Targeted Therapies
B-RafB-RafV600E V600E positive metastatic melanomapositive metastatic melanoma
Resistance to Targeted TherapiesResistance to Targeted Therapies
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
Resistance to Targeted TherapiesResistance to Targeted Therapies
Main developments in Oncology since the turn of the Main developments in Oncology since the turn of the CenturyCentury
Introduction: Key Developments in OncologyIntroduction: Key Developments in Oncology
#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
Cancer GenomesCancer Genomes
Pancreatic Ductal Adenocarcinoma: Exon Pancreatic Ductal Adenocarcinoma: Exon sequencingsequencing
Cancer GenomesCancer Genomes
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
Pancreatic Ductal Adenocarcinoma: Exon Pancreatic Ductal Adenocarcinoma: Exon sequencingsequencing
Cancer GenomesCancer Genomes
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
Introduction: Key Developments in OncologyIntroduction: Key Developments in Oncology
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.
Immunotherapy and CancerImmunotherapy and Cancer
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
Immunotherapy and CancerImmunotherapy and Cancer
Metastatic Metastatic MelanomaMelanoma
Tum
or re
spon
se (%
)Tu
mor
resp
onse
(%)
Patients treated with Pembrolizumab (anti-PD1)Patients treated with Pembrolizumab (anti-PD1)
Immunotherapy and CancerImmunotherapy and Cancer
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)
Immunotherapy and CancerImmunotherapy and Cancer
Non-Squamous NSCLC (Borghaei et al., NEJM, Sept 2015)Non-Squamous NSCLC (Borghaei et al., NEJM, Sept 2015)
Immunotherapy and CancerImmunotherapy and Cancer
Non-Squamous NSCLC (Borghaei et al., NEJM, Sept 2015)Non-Squamous NSCLC (Borghaei et al., NEJM, Sept 2015)
Immunotherapy and CancerImmunotherapy and Cancer
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
Immunotherapy and CancerImmunotherapy and Cancer
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
Immunotherapy and CancerImmunotherapy and Cancer
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!!