dianas terapeúticas: ser o no ser, esa es la cuestión en ...€¦ · shifting the paradigm ....

Dianas terapeúticas: ser o no ser, esa es la cuestión En Oncología

Miquel Àngel Seguí Palmer

Dianas terapeúticas en Oncología

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Targeted therapy involves developing drugs that block cancer cell proliferation, promote cell cycle regulation or induce apoptosis or autophagy and targeted delivery of toxic substances specifically to cancer cells to destroy them. Targeted therapy involves the use of monoclonal antibodies or oral small drugs


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Two images of a Breast Cancer

The standard paradigm of classifying patients by histology alone, and treating large unselected groups of patients with the same treatment is unlikely to dramatically improve outcomes.

A different approach entails matching molecular classification with targeted therapy.


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The shift of paradigm: towards molecular subsets of cancers


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The shift of paradigm: molecular alterations shared in several cancers


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Expression profile Identification of Breast Tumor Intrinsic Subtypes

Carey, L. A. et al. JAMA 2006;295:2492-2502

The challenge that arises from the molecular subclassification of malignancies is that molecularly distinct cancer subtypes may each become orphan diseases.


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Targeted therapy aims at delivering drugs to particular genes or proteins that are specific to cancer cells or the tissue environment that promotes cancer growth.


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Traditional cytotoxic chemotherapy works primarily through the inhibition of cell division

Targeted therapy blocks the proliferation of cancer cells by interfering with specific molecules required for tumor development and growth


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Targeted therapies vs. standard chemotherapy


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Targeted therapies differ from standard chemotherapy in several ways:

• Targeted therapies act on specific molecular targets that

are associated with cancer, whereas most standard chemotherapies act on all rapidly dividing normal and cancerous cells.

• Targeted therapies are deliberately chosen or designed to interact with their target, whereas many standard chemotherapies were identified because they kill cells.

• Targeted therapies are often cytostatic (that is, they block tumor cell proliferation), whereas standard chemotherapy agents are cytotoxic (that is, they kill tumor cells).


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Unlike traditional cytotoxic chemotherapies that have frequently entered the clinic without exact knowledge of their mechanism of action and have been discovered and developed on the basis of their ability to interfere with cell division, molecularly designed drugs, on the other hand, have been developed based on a particular known molecular target. Thus, a primary goal of molecularly targeted cancer therapies is to fight cancer with more precision than traditional chemotherapy regimens and hopefully with the additional benefit of less adverse side effects for the patient in treatment.


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Myth: Targeted therapy is new (or what were we thinking?)

• DNA is not a bad target.

• Tubulin is a very good target.

• Specific receptor targeting: tamoxifen etc.


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• A superficial definition of targeted therapy implies that it is a therapy that is used to target a specific molecular aberration or genetic anomaly. The targeting of HER2 overexpression with the monoclonal antibody, trastuzumab is a example of targeted treatment .

• By contrast, we could use bevacizumab as an example, hailed as an agent that targets VEGF-A. To date, however, we have been unable to identify biomarkers that can be used to select a population primed for therapeutic response to anti-VEGF therapy.

• Finally, a given ‘targeted’ therapeutic agent might impact multiple targets (for example, sorafenib, which is a multikinase inhibitor) instead of a single one. Hence, targeted therapy cannot always be defined as having single-target specificity.


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(1) angiogenic blood vessels (e.g. Bevacuzimab) (2) re-education of the immune system (e.g. Ipilimumab), (3) extracellular domains of transmembrane receptors (e.g. Cetuximab and Trastuzumab) (4) intracellular targets, such as TK domains and downstream signaling (e.g. Imatinib). (5 &6) nuclear signaling (e.g. SERMs).

Røsland GV, Engelsen AS. Basic Clin Pharmacol Toxicol. 2015;116(1):9-18


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What types of targeted therapies are available?

• Hormone therapies

• Signal transduction inhibitors

• Gene expression modulators

• Apoptosis inducers

• Angiogenesis inhibitors

• Immunotherapies

• Monoclonal antibodies that deliver toxic molecules


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Targeted therapies in breast cancer


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Targeted therapies in non-small cell lung cancer


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Adjuvant Trastuzumab in Her2+ Breast Cancer

Crizotinib in ALK+ metastatic NSCLC


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Erlotinib in Advanced Pancreatic Cancer

Bevacizumab in metastatic Breast cancer


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The Increasing Precision on Anticancer Therapeutics


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Limitations of Targeted Therapies

• Tumor Heterogeneity

• Molecular Evolution and Resistance

• Undruggable Targets

• Technical Challenges

• Need for New Trial Designs

• Pharmacological Challenges


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Targetable genomic alterations in breast cancer


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It should be noted that side effects of some molecularly targeted drugs are not insignificant, and neither are the treatment costs, highlighting the importance of identifying reliable biomarkers to predict which patients will benefit from a particular treatment.


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Over 20 tumor types are being treated with new medicines that have been launched in the past five years


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Growth of the Late Phase Oncology Pipeline, 2005-2015


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Patients in only 6 countries had access to at least half of the 49 new oncology medicines launched 2010-2014


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Shifting the Paradigm


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THERAPEUTIC TARGETING OF THE HALLMARKS OF CANCER


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“Doctors have always recognized that every patient is unique, and doctors have always tried to tailor their treatments as best they can to individuals.

What if matching a cancer cure to our genetic code was just as easy, just as standard?

What if figuring out the right dose of medicine was as simple as taking our temperature?”

Precision Medicine


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The use of an individual patient’s molecular information (including genomics and proteomics) to inform diagnosis, prognosis, treatment and prevention of cancer for that patient.

Precision Medicine


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Precision Medicine


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“The right patient, the right disease, the right drug”


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Oncology is at the frontline of personalised medicine, moving beyond the previous model of giving cancer therapeutics based on trials of largely unselected patients beyond a simple phenotypic marker, to leading the way in utilising the molecular profile of an individual’s cancer genome to optimise their disease management.


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Novel clinical trial designs to test precision-medicine approaches in cancer


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Matching Each Cancer with Individually Targeted Therapy


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A small subset of cancer patients with actionable mutations could be expected to benefit from targeted therapy with either commercially available drugs or drugs in clinical trials. Although the response rate to targeted therapy could be improved based on personalized biomarker selection, there remain many driver mutations for which effective targeted drugs are not available.


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• Driving somatic genetic mutations causing cancer development/progression are the scientific basis of the development of molecularly targeted drugs.

• Targeted therapies, which include monoclonal antibodies and small molecule inhibitors, have significantly changed the treatment of cancer over the past 10 years.

• The mechanisms of action and toxicities of targeted therapies differ from those of traditional cytotoxic chemotherapy. Targeted therapies are generally better tolerated than traditional chemotherapy, but they are associated with several adverse effects.

Take-home messages…...(1)


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• Molecular genetics converts severe frequent cancers into specific rare cancers with specific treatment. The selection of patients for targeted therapy remains a challenge because we lack reliable biomarkers to predict activity for most of the targeted agents.

• Traditional methodologies applied for drug development are likely inappropriate for new targeted agents.

• Targeted therapy has raised new questions about the tailoring of cancer treatment to an individual patient’s tumor, the assessment of drug effectiveness and toxicity, and the economics of cancer care.

• Personalised medicine, will lead the way in utilising the molecular profile of an individual’s cancer genome to optimise their disease management.

Take-home messages…...(2)


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dianas terapeúticas: ser o no ser, esa es la cuestión en ...€¦ · shifting the paradigm ....

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