This document discusses five key developments in oncology since 2000:
1. The rise of targeted therapies that selectively inhibit molecular cancer drivers
2. Tumor stratification based on driver mutations and molecular profiles to select targeted treatments
3. Emergence of resistance to targeted therapies due to secondary mutations or activation of alternative pathways
4. Cancer genome sequencing revealing high mutation burdens and heterogeneity within tumors
5. Discovery of tumor heterogeneity with subclones evolving over time, challenging targeted treatment approaches
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Mariano Barbacid-El cáncer como consecuencia del envejecimiento
1. MOLECULAR ONCOLOGY, CANCERMOLECULAR ONCOLOGY, CANCER
GENOMES AND PRECISION MEDICINEGENOMES AND PRECISION MEDICINE
MOLECULAR ONCOLOGY, CANCERMOLECULAR ONCOLOGY, CANCER
GENOMES AND PRECISION MEDICINEGENOMES AND PRECISION MEDICINE
MARIANOMARIANO
BARBACIDBARBACIDCENTRO NACIONAL DE INVESTIGACIONESCENTRO NACIONAL DE INVESTIGACIONES
2. Main developments in Oncology since the turn of the CenturyMain developments in Oncology since the turn of the Century
#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
3. Novel Drugs in Oncology: FDA ApprovalsNovel Drugs in Oncology: FDA Approvals
Year
80 85 90 95 00 05
5
4
3
1
New(nometoo’s)DrugsApprovedby
theFDAonaperyearbases
Cytotoxic agents
Biologicals
Targeted drugs
Vaccines
10
2
IF
Glev
Her
Ritux
4. Main developments in Oncology since the turn of the CenturyMain developments in Oncology since the turn of the Century
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
7. Main developments in Oncology since the turn of the CenturyMain developments in Oncology since the turn of the Century
#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
8. Resistance to Targeted TherapiesResistance to Targeted Therapies
Gleevec and CMLGleevec and CML
9. EGFR mutant NSCLCEGFR mutant NSCLC
Resistance to Targeted TherapiesResistance to Targeted Therapies
12. Mechanism of Drug Resistance.
B-RafB-RafV600EV600E
positive Metastatic Melanoma treated with Vemurafenibpositive Metastatic Melanoma treated with Vemurafenib
Before treatmentBefore treatment After treatmentAfter treatment
Resistant toResistant to
VemurafenibVemurafenib
Resistance to Targeted TherapiesResistance to Targeted Therapies
13. Main developments in Oncology since the turn of the CenturyMain developments in Oncology since the turn of the Century
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
14. 1.0 mutations por megabase = 3.000 mutations per tumor
Cancer GenomesCancer Genomes
18. Main developments in Oncology since the turn of the CenturyMain developments in Oncology since the turn of the Century
#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
20. 41 years
13 years
2001
1998
Targeted Therapies: The long road to drug developmentTargeted Therapies: The long road to drug development
GleevecGleevec
HerceptinaHerceptina
17 years
9 years
4 years
2011
2011
2011
Olapari
b
Olapari
b
VemurafenibVemurafenib
CrizotinibCrizotinib
21. Immunotherapy and CancerImmunotherapy and Cancer
Scientists have always wonder why our immune system is not capable of recognizeScientists have always wonder why our immune system is not capable of recognize
and reject our tumorsand reject our tumors
In fact, for many years they have tried to develop antibodies against “tumorIn fact, for many years they have tried to develop antibodies against “tumor
antigens”antigens”
Unfortunatey, tumor plasticity allows tumors to evolve tumor variants that noUnfortunatey, tumor plasticity allows tumors to evolve tumor variants that no
longer express such “tumor antigenes” since these antigen are not essential forlonger express such “tumor antigenes” since these antigen are not essential for
tumor maintenancetumor maintenance
In the 90s some scientists decide to potentiate the adaptive response byIn the 90s some scientists decide to potentiate the adaptive response by
stimulating the cytotoxic T lymphocytes using IL-2 as well as other cytokinnes.stimulating the cytotoxic T lymphocytes using IL-2 as well as other cytokinnes.
Unfortunatley, this approach, although obtained a few responses specially in youngUnfortunatley, this approach, although obtained a few responses specially in young
people, had to be abandoned due to its high toxicity since the over-activated Tpeople, had to be abandoned due to its high toxicity since the over-activated T
lymphocytes also attacked our nomral tissues.lymphocytes also attacked our nomral tissues.
22. During the last few years, scientists appear to have discover a way t manipulate ourDuring the last few years, scientists appear to have discover a way t manipulate our
immune system to fight, at least certain cancers, mainly matastatic melanoma.immune system to fight, at least certain cancers, mainly matastatic melanoma.
The key discovery has been, not to stimulate our immune systme, butThe key discovery has been, not to stimulate our immune systme, but to inhibit itsto inhibit its
desactivationdesactivation
Our organism is able to mount an immune response to defend us from infections byOur organism is able to mount an immune response to defend us from infections by
potentiating thepotentiating the innateinnate (mainly(mainly dendritic cells, NK cells, macrophages, neutrophils,
etc.) and theand the adaptiveadaptive (B and T lymphocytes) responses. Yet, at the same time, our(B and T lymphocytes) responses. Yet, at the same time, our
organisms has developed sophysticated mechanisms to dampen this response onceorganisms has developed sophysticated mechanisms to dampen this response once
the infection has subsided.the infection has subsided.
Thus, some scientists decided to block those proteins implicated in deactivation ofThus, some scientists decided to block those proteins implicated in deactivation of
the cytotoxic T lymphocytes, mainly CTLA-4 and PD1, now part of a complexthe cytotoxic T lymphocytes, mainly CTLA-4 and PD1, now part of a complex
regulatory mechanism known as the “regulatory mechanism known as the “immune checkpointsimmune checkpoints”.”.
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 auto-Indeed, without these inhibitory mechanims we may end up developong auto-
immune or immunedegenerative diseases.immune or immunedegenerative diseases.
Immunotherapy and CancerImmunotherapy and Cancer
23. Based on these studies, several pharmaceutical companies have developedBased 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 MAbThe 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 lymphocyteActivated T lymphocyte
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
24. Metastatic MelanomaMetastatic MelanomaMetastatic MelanomaMetastatic Melanoma
Tumorresponse(%)Tumorresponse(%)Tumorresponse(%)Tumorresponse(%)
Patients treated with Pembrolizumab (anti-PD1)Patients treated with Pembrolizumab (anti-PD1)Patients treated with Pembrolizumab (anti-PD1)Patients treated with Pembrolizumab (anti-PD1)
Immunotherapy and CancerImmunotherapy and Cancer
26. Non-Squamous NSCLC (Borghaei et al., NEJM, Sept 2015)Non-Squamous NSCLC (Borghaei et al., NEJM, Sept 2015)Non-Squamous NSCLC (Borghaei et al., NEJM, Sept 2015)Non-Squamous NSCLC (Borghaei et al., NEJM, Sept 2015)
Immunotherapy and CancerImmunotherapy and Cancer
27. Non-Squamous NSCLC (Borghaei et al., NEJM, Sept 2015)Non-Squamous NSCLC (Borghaei et al., NEJM, Sept 2015)Non-Squamous NSCLC (Borghaei et al., NEJM, Sept 2015)Non-Squamous NSCLC (Borghaei et al., NEJM, Sept 2015)
Immunotherapy and CancerImmunotherapy and Cancer
28. These results have been generated based on just two immune checkpoints thatThese results have been generated based on just two immune checkpoints that
regulate the immune response elicited by T cells, CTLA4/B7.1 and PD1/PDL1regulate the immune response elicited by T cells, CTLA4/B7.1 and PD1/PDL1
Immunotherapy and CancerImmunotherapy and Cancer
29. Since there are many other immune checkpoints it is quite possible thatSince there are many other immune checkpoints it is quite possible that
immunotherapy might expand its use to the treatment of many other types of cancerimmunotherapy might expand its use to the treatment of many other types of cancer
Immunotherapy and CancerImmunotherapy and Cancer
30.
31.
32. 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
34. Tipos de cáncer: Incidencia vs. MortalidadTipos de cáncer: Incidencia vs. Mortalidad
MortalityMortality
35. 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!!
Editor's Notes
Figure 2. Mechanism of Drug Resistance. Panel A shows the crystallographically determined binding of erlotinib to wild-type EGFR, whereas Panel B shows how the T790M mutation leads to steric hindrance of erlotinib binding owing to the presence of the bulkier methionine side chain (orange) in the ATP-kinase–binding pocket. Panel C shows the steric hindrance in the predicted complex of gefitinib and EGFR with the T790M mutation. Panel D shows the predicted binding of CL-387,785 to EGFR with the T790M mutation (structural change introduced by the T790M mutation shown in orange).