Abstract
The AACR–NCI–EORTC international conference held on 15–19 November 2009 in Boston (MA, USA) was a unique opportunity to discuss basic and translational research and the therapeutic implications in relation to molecular targets in cancer. The conference was divided into plenary and educational sessions, keynote presentations, special lectures, proffered papers and poster sessions. This conference is a joint effort of prestigious organizations (EORTC, NCI and AACR) that have been involved for several years in basic and clinical cancer research. In this report, we will summarize the main topics discussed at this conference.
An educational session held at the beginning of the conference emphasized the challenges in measuring and using the targets in cancer therapeutics. Hormone receptors, HER2 and EGF receptor as predictive markers were the biomarkers most discussed at the session. All of the speakers emphasized the importance of the standardization of the assays and the interpretation criteria of the results, which are essential for optimal clinical decision making.
The second educational session covered targets in cancer prevention, a new topic in the conference. Classical targets were reviewed, as well as those in clinical trials performed so far.
New molecular targets are emerging. The major issue under clinical investigation is how to identify women that will respond to preventive therapy. Another important goal is to develop agents with an optimal therapeutic index. For example, metformin, a drug used to target energy imbalance is currently the basis of ongoing clinical trials.
Two outstanding keynote lectures were presented. The first was about the resistance to targeted agents, which is unfortunately a clinical reality. Acquired resistance to kinase inhibitors in chronic myeloid leukemia and to EGF receptor and HER2 inhibitors in non-small-cell lung cancer and breast cancers are two examples. Interestingly, HER3 has emerged as a cause of resistance to anti-HER2 drugs opening the way to investigate the combination of anti-HER2 and anti-HER3. We note that epigenetics could explain some mechanisms of resistance, such as with endocrine therapy. DNA sequencing of tumors, to discover new mutations that cause the resistance, and a close collaboration with chemists, to develop new agents targeting these mutations, might help to overcome some of the resistance to these drugs.
The second speaker emphasized the importance of identifying tumor-specific targets. The role of PARP in the repair process of BRCA mutated tumors and triple-negative breast cancers and the hedgehog pathway in basal-cell carcinoma are examples of tumor-specific targets. The recent development of active PARP and hedgehog pathway inhibitors offer unique opportunities for patients suffering from these diseases.
Moving on to the plenary sessions, important topics were discussed.
Genetically engineered mouse models for cancer offer an excellent tool to discover and test novel therapeutics, to understand drug resistance and tumor maintenance and to dissect several specific pathways, such as PI3K. The PI3K pathway was the focus of a separate plenary session as this pathway is a key element in tumor cell metabolism and growth and it is involved in drug resistance to targeted agents, including endocrine therapy. PI3K inhibitors are under active clinical investigation alone and in combination.
In recent years, tumor cell metabolism has become a target in cancer therapeutics. Cell metabolism is a huge and complex process. The targets are multiple and need to be validated. Tumor cell death under metabolic stress needs to be elucidated. The role of extracellular matrix on the control of tumor cell metabolism seems to be important. Finally, tumor cell metabolism in response to chemotherapy, molecular-targeted therapies and to specific agents interfering with the cancer cell metabolism needs to be further understood and developed.
In this conference, the cancer genome and epigenome were the focus of two specific plenary sessions. Pharmacogenomics is currently in the midway between basic science and clinical practice. Many translational studies are ongoing in different tumor types and randomized clinical studies to validate this approach are recruiting in breast cancer. As far as new anticancer drug development is concerned, gene signatures for guiding the use of targeted and cytotoxic agents are also under investigation.
Inhibition of chromatin-modifying enzymes (e.g., histone deactylase inhibitors and hypomethylating drugs) is the focus of preclinical and clinical testing. The outcome of this research is unclear at this moment. Nevertheless, this research is of the utmost importance, since the majority of cancers harbor epigenetic modifications rather than germline changes. These modifications play a role not only in carcinogenesis but also in drug sensitivity and resistance.
To target only the tumor cell and to avoid the tumor microenvironment is the ‘Holy Grail’ of cancer therapy. Inflammation elements appeared to be the key in tumor growth and progression in addition to angiogenesis and immune function. Targeting the tumor environment is consequently essential. The synergy in targeting tumor cell and tumor microenvironment is probably a prerequisite to the success of cancer therapy.
Other important topics discussed at this conference are summarized as follows:
The proof of concept clinical trial designs in oncology were discussed. Clearly, innovative and ‘individualized’ early clinical trial designs are needed. Beyond discovery, the validation of biomarkers is an essential parameter to the success of this approach.
In vivo imaging of targets, signal transduction pathways and tumor responses were debated. MRI, spectroscopy, PET and optical imaging are among several tools used currently in early clinical investigation of new anticancer agents.
The role of circulating tumor cells and the concept of tumor dormancy were also discussed. In fact, circulating tumor cells could be targets for cancer therapy, as well as pharmacodynamic and/or predictive biomarkers. For the moment, it is unclear what the role of circulating tumor cells will be in clinical practice and they are still considered investigational.
The development of specific protein kinase inhibitors was reported at the conference. The lessons learned from the development of oncogene-selective B-Raf inhibitor in melanoma, the ALK inhibitor in a small molecular subtype of non-small-cell carcinoma and the JAK2 inhibitors in myeloproliferative neoplasms illustrated well the importance of the target, the tumor molecular subtype, patient selection and the optimal conduct of the early clinical trial.
Monoclonal antibodies are nowadays considered among the most active targeted approaches in hematological malignancies and solid tumors. Their efficacy is mainly proven in combination with cytotoxic agents. New variants of monoclonal antibodies are under development. The aims of these new formulations are to improve the immunogenicity or to use it as a delivery tool of toxic anticancer agents (e.g., T-DM1). New therapeutic antibody targets are also in development. For example, CD47 seems to be an adverse prognostic factor and a therapeutic target of human acute myeloid leukemia stem cells.
Finally, handling the side effects related to targeted therapies is important to preserve the quality of life of the patients and to optimize drug delivery. In summary, cardiac dysfunction and vascular complications emerged as serious side effects of HER2/neu inhibitors, antiangiogenic drugs and multitargeted kinase inhibitors. Other side effects included among others renal toxicity (proteinuria), skin, gastrointestinal and liver toxicities. These side effects imply a better dialog is required between oncologists and specialists from other disciplines to handle these toxicities. Education of the oncologists on how to prevent and manage these side effects, as well as optimally informing patients, is of utmost importance in order to optimally deliver these agents. In the near future, pharmacogenetics might help to predict some of these cumbersome side effects.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.