New Medicine's Oncology KnowledgeBASE (nm/OK) residing at http://nmok.net became available on the Internet 10 years ago and, since then, the oncology field has evolved into one of the most challenging, complex and promising drug development sectors, both in terms of its potential contribution to medicine and to its market opportunities.
The global market of oncology drugs is forecast to reach $80 billion by the middle of this decade, more that double its current levels. Currently, there are over 725 anticancer drugs in clinical development and at least another 300-500 in preclinical and research stages. Over 3,500 novel approaches have been evaluated clinically or preclinically in the last decade. Currently, more than 10,000 clinical trials with novel and approved agents, alone or in combination, are ongoing with over 12% having entered phase III status. Globally, over 1,000 distinct commercial entities are developing oncology drugs or have technologies applied to this sector
However, although the pace of developments in basic and applied research in cancer by academia and industry has reached unprecedented levels, and numerous novel agents have been approved and launched, these advances have yet to translate to significant gains in the clinic, particularly in the treatment of advanced or metastatic disease.
On the bright side there are many very promising developments on the horizon deriving from better understanding of the process of neoplastic transformation; advances in basic research concerning the role of molecular effectors in carcinogenesis; better imaging, diagnostic, prognostic, theragnostic, pharmacogenomic and disease monitoring approaches; advances in analytical techniques and drug discovery/design approaches; and novel drug delivery systems, among others, that may yield in the coming years much needed effective treatments for this deadly disease. .
Novel targets and mechanisms
The complexity of the process of malignant transformation is staggering. Cancer cells harbor numerous aberrantly expressed molecular moieties. Also, tumor cells are closely related but genetically distinct in the same host. Redundancy in effectors and pathways allows escape from the effects of highly selective targeting of single or multiple moieties, and drug resistance prevents long term benefits. Nevertheless, targeted agents represent the most sought after approach to cancer therapy. Several hundred cancer-related targets have been identified and over 160 distinct have been evaluated in clinical trials but few of these efforts led to commercialized products, with none providing a bona fide 'cure'. Currently, over 210 novel targeted agents are being evaluated in phase I clinical trials, and many have entered phase III trials. Some of the newer research avenues in drug development may lead to better management of this disease.
-- Cancer stem cells (CSC)
Although controversial, inconsistently defined, and yet to be conclusively proven as a therapeutic target in solid tumors, the possible existence of CSC is becoming more and more attractive as CSC may provide a well defined target within tumor cells. Proponents define CSC as a subset of tumor cells responsible for driving tumor growth and recurrence that are resistant to many existing anticancer therapies. Doubters believe that there is no such thing as a CSC but normal cells spontaneously reprogram themselves into a malignant phenotype. Nevertheless, several companies are targeting putative CSC in preclinical and clinical evaluations.
-- Synthetic lethality
Synthetic lethality exploits potential damage to pathways that depend on normal 2-gene interactions. Although cells survive in the presence of mutations in either gene, damages in both genes in separate semi-redundant or co-operating pathways or in the same pathway, kill the cells. Synthetic lethality is being investigated in clinical trials using poly (ADP-ribose) polymerase (PARP) inhibition in patients with breast cancer harboring BRCA1/BRCA2 mutations.
-- Chemical reactions/metabolism of cancer cells
In contrast to targeting unique molecular effectors in cancer cells, interfering with chemical/metabolic reactions within the cell, shared by all tumor cells, represents a universal approach to tumor cell killing and may overcome the challenge of molecular heterogeneity of tumor cells and mechanisms of resistance hampering the effectiveness of targeted drugs. One approach exploits biochemical alterations in the conversion of glucose to energy occurring in many types of cancer cells. Restricting glucose uptake by cancer cells would starve tumors; it has been demonstrated that the antidiabetic drug metformin that suppresses glucose production in the liver halves the risk of developing pancreatic or colon cancer. Another approach in starving tumors is by targeting mTOR that regulates cell growth, proliferation and survival by impacting on protein synthesis and transcription. Two agents targeting mTOR are already on the market and more than 10 are in clinical trials with one having entered phase III clinical development.
-- Epithelia to mesenchymal transition (EMT)
In EMT, epithelial cells are transformed into mesenchymal-like cells in a process that requires alterations in morphology, cellular architecture, adhesion, and migration ability. Malignant mesenchymal cells that move individually, often in an aggressive, uncontrolled fashion, represent an important step in invasiveness and metastasis. Phenotypic markers for an EMT include an increased capacity for migration and 3-dimensional invasion, as well as resistance to anoikis/apoptosis. There are numerous cancer cell factors promoting EMT and inhibition of EMT may reverse resistance of cancer cells to targeted therapies. Targeting EMT may increase the effectiveness of inhibitors of the ErbB pathway currently accounting for a large global market with over 30 agents in clinical development.
-- RNA interference (RNAi) and gene silencing
RNAi and gene silencing present a unique promise as cancer therapeutics but their effectiveness in oncology has yet to be demonstrated in the clinic. Numerous microRNA (miRNA or mir), the regulatory molecules that negatively control gene expression by binding to complementary sequences on target mRNA, have been identified as potential cancer therapeutics.
Epigenetics determine the expression of genes in health and disease. The epigenome consists of a number of enzymes that turn genes off and on. Unlike mutations that alter gene structure, epigenomic activity occurs outside the gene, and epigenetic changes may reverse a gene's aberrant activity without the need to affect the gene itself. Epigenomics is at the forefront of approaches in cancer management, as it has been demonstrated that inappropriate epigenetic activity contributes significantly to cancer causation and growth. .
-- Tumor microenvironment (seed and soil)
One of the key challenges of anticancer drug development is determining the influence of the tumor microenvironment (stroma) in tumor cell proliferation and metastasis. The interaction between the tumor and the host involves the complete host system and includes immune responses, angiogenesis, extracellular matrix (ECM) support, and lymphatic and vascular tumor cell transport . Interfering with the tissue microenvironment has been challenging as illustrated by the limitations of angiogenesis inhibition.
Patient selection based on verified tumors' molecular profile, personalized medicine, and advances based on in vitro testing (IVT)
Patient selection for treatment options is becoming mainstream because the validity of molecular profiling in predicting treatment outcomes has been demonstrated in numerous settings. Nearly every trial of targeted agents includes in its design some type of molecular profiling. However, despite the massive amount of information in this area, personalizing treatment in cancer has yielded only a few clear cut benefits in the clinic. One of the chief problems in patient selection for targeted therapies may be attributed to the heterogeneity among tumor subclones in the same host. There is unquestioned evidence that solid tumors are polyclonal malignancies. Therefore, personalized treatment may turn out to be a much more involved approach, requiring that patients are treated with drug cocktails inhibiting the various activated pathways in a given patient.
The IVT sector has grown exponentially in the last decade. Over 250 companies are developing some type of IVT in cancer. IVT include screening tests, diagnostics, pharmacogenomics, prognostics, disease monitoring tests, theragnostics, toxicogenomics, etc. For instance, over 30 companies have development programs in IVT in ovarian cancer, 42 in lung cancer, 19 in bladder cancer, etc.
Trials combining novel targeted agents
Targeted agents currently constitute the majority of novel drugs entering clinical trials. Over 200 novel targeted drugs are in phase I clinical trials, mostly small molecule protein kinase inhibitors or monoclonal antibody (MAb)-based blockers of cell surface receptors. These newer agents are addressing over 160 distinct molecular moieties shown to play a role in malignancy. Novel targeted agents are usually evaluated as monotherapies or in combination with approved/marketed agents. It is anticipated that in this decade, such agents will also be clinically evaluated in combinations with each other. Such an endeavor will take clinical development to a new level of complexity but may also have surprisingly beneficial results.
Protein/peptide-based agents versus small molecule drugs
Small molecule drugs have dominated new drug development in the last part of the 2000s primarily because of they are orally available and easier to produce; yet overall, biologicals dominate the market. Some of the most successful agents both in the clinic and the market, including such blockbusters as bevacizumab (Avastin; Genentech) and rituximab (Rituxan; Biogen Idec), among others, are biologicals. Currently, over 130 MAb-based agents are in clinical development with 20 having entered phase III clinical trials.
Antibody engineering technologies and novel immunoconjugates, radioimmunoconjugates, fusion proteins, and antibody-drug conjugates (ADC)
Monoclonal antibodies (MAb) are the backbone of the oncology drug sector. No fewer than 125 companies are focusing in oncology applications of MAb in this ever advancing field. The attractiveness of MAb is their ability to target surface receptors with exquisite specificity and also, in many cases, stimulate the immune system to destroy cells expressing such receptors. In the past decade over 650 distinct MAb have been evaluated in oncology. Although effective as signal transaction inhibitors on their own, the targeted specificity of MAb makes them excellent ferries of drugs/toxins, and radioisotopes to cancer cells. Such an application of MAb is currently exploited in antibody drug conjugates (ADC), a burgeoning area of drug development with 11 drugs in clinical trials with one in phase III.
Although the human immune system is capable of raising an immune response against many cancer types, it fails to eradicate cancer in most patients, possibly because of negative regulation of the immune system by the tumor. Immune surveillance is the major mechanism by which malignant cells are recognized and eliminated by the immune system before they can develop into clinically detectable tumors. Although, immune system failure may contribute to the survival and proliferation of cancer cells, it is now theorized that tumors adopt ways for evading eradication by the immune system. After several failures of cancer immunotherapies in late phase trials, interest has been rekindled in this area by several positive developments, primarily by favorable results with Dendreon's prostate vaccine Provenge. Over 125 immunotherapeutics/vaccines are in clinical development, with many demonstrating favorable activity with low toxicity.
After many years in development virotherapy is beginning to show effectiveness in the clinic. As many 32 distinct oncolytics have been investigated over the last 10 years with 11 agents currently in clinical development in various cancer indications.
Cytotoxics remain the backbone of cancer treatment for both advanced disease and in adjuvant and neoadjuvant settings. Nearly every approved and most novel agents are being combined with a cytotoxic regimen. Therefore, considerable effort is dedicated to improving every aspect of cytotoxic chemotherapy. In the past decade over 663 distinct cytotoxics were evaluated preclinically and clinically with 228 currently under development; 98 incorporate some type of a delivery system and 32 are prodrugs. Among 195 currently in clinical development, 32 novel agents have entered phase III clinical trials. Many clinical programs involve approaches to improve the performance and reduce the non-specific toxicity of leading marketed chemotherapeutics as well as of several experimental drugs that were withdrawn from development because of unacceptable toxicity and formulation difficulties.
Advances in drug delivery, including nanotechnology
Drug delivery is the second most important challenge of targeted therapeutics after proof of efficacy in vitro and in vivo, and perhaps one of the key reasons drugs that perform well in small animals models fail in humans. New therapeutic approaches such as microRNA inhibitors reignited the quest for effective drug delivery systems. Nanotechnology is currently the holy grail of drug delivery in oncology being pursued by 40 distinct entities, each developing its own version of this promising approach, which may revitalize the cytotoxic drug sector that is still the standard treatment for almost all types of advanced disease and enable the clinical application of such novel technologies as RNA interference (RNAi).
Addressing specific cancer indications
Literally thousands of specific clinical indications are being investigated in clinical trials based on tumor primary site, cellular morphology, disease stage, patient characteristics (age, performance status, health status), treatment options and line of therapy, tumor molecular profile, etc. are being investigated in the clinic. Gradually, cancer is being defined at the gene level, creating numerous subcategories of clinical indications within each major cancer currently defined by the affected organ. It is conceivable that these narrow indications will guide approval and determine the commercial opportunity for many agents.