TRANSLATIONAL THERAPEUTICIS AND DISCOVERIES
Cancer Research and Life Foundation supports the research and development of novel therapies that can disrupt the current standard of care model.
Here are some examples in the oncologist history that we recall being disruptive therapies:
1940s- During World War II, naval personnel who were exposed to mustard gas during military action were found to have toxic changes in the bone marrow cells that develop into blood cells. During that same period, the US Army was studying a number of chemicals related to mustard gas to develop more effective agents for war and also develop protective measures. In the course of that work, a compound called nitrogen mustard was studied and found to work against a cancer of the lymph nodes called lymphoma. Meclorethamine- First drug extracted from Mustard Gas, where was called the chemotherapy. The World War with all deaths and misery brought a discovery of chemotherapy agents to man. Soldiers who were exposed to this lethal agent, AND had leukemias, ( blood cancer) they did not die, and in fact got better. To be in the battle field with Leukemia, and be exposed to Mustard Gas, could be worse someone can wish, but these folks were lucky to have leukemia, as the lethal gas saved them! Later the agent Meclorethamine was extracted from the chemical and used (currently) for treatment of blood cancer.
This agent served as the model for a long series of similar but more effective agents (called alkylating agents) that killed rapidly growing cancer cells by damaging their DNA.
Use of Natural Compounds in Cancer:
Not long after the discovery of nitrogen mustard, Sidney Farber of Boston demonstrated that aminopterin, a compound related to the vitamin folic acid, produced remissions in children with acute leukemia. Aminopterin blocked a critical chemical reaction needed for DNA replication. That drug was the predecessor of methotrexate, a cancer treatment drug used commonly today.
75 percent of all chemotherapies are made from natural products.
For over 40 years, natural products have served us well in combating cancer. The main sources of these successful compounds are microbes and plants from the terrestrial and marine environments. The microbes serve as a major source of natural products with anti‐tumour activity. A number of these products were first discovered as antibiotics. Another major contribution comes from plant alkaloids, taxoids and podophyllotoxins. A vast array of biological metabolites can be obtained from the marine world, which can be used for effective cancer treatment. The search for novel drugs is still a priority goal for cancer therapy, due to the rapid development of resistance to chemotherapeutic drugs. In addition, the high toxicity usually associated with some cancer chemotherapy drugs and their undesirable side‐effects increase the demand for novel anti‐tumour drugs active against untreatable tumours, with fewer side‐effects and/or with greater therapeutic efficiency.
Of the 140 anti‐cancer agents approved since 1940 and available for use, over 60% can be traced to a natural product. Of the 126 small molecules among them, 67% are natural in origin (Cragg and Newman, 2005). In 2000, 57% of all drugs in clinical trials for cancer were either natural products or their derivatives (Cragg and Newman, 2000). From 1981 to 2002, natural products were the basis of 74% of all new chemical entities for cancer. Of the 225 natural product‐based drugs in various stages of clinical testing in 2008 mentioned above (Harvey, 2008), the therapeutic categories targeted included 86 for cancer.Compounds with anti‐tumour activity belong to several structural classes such as anthracyclines, enediynes, indolocarbazoles, isoprenoids, polyketide macrolides, non‐ribosomal peptides including glycopeptides, and others. Most of the polyketides are produced by bacteria and fungi (Rawls, 1998; Xue et al., 1999). They include a number of anti‐tumour drugs such as taxol, which is made by both plants and fungi.
Some approved plant‐derived anti‐tumour compounds.
Vinblastine (Velban)Vincristine (Oncovin)EtoposideTeniposideTaxol (paclitaxel)Navelbine (Vinorelbine)Taxotere (Docetaxel)Camptothecin (Camptosar, Campto)Topotecan (Hycamtin)Irinotecan
It is clear that the future success of the pharmaceutical industry depends not only on high‐throughput screening and combinatorial chemistry, but on the combining of complementary technologies, such as natural product discovery, genomics, proteomics, metabolomics, metagenomics, structure‐function drug design, semi‐synthesis, recombinant DNA methodology, genome mining and combinatorial biosynthesis, at a nut shell, translational therapeutics and discoveries…This is where CRL Foundation invests most of it’s efforts to create the platform for most novel technologies in cancer.
1956 – when methotrexate was used to treat a rare tumor called choriocarcinoma. Over the years, chemotherapy drugs (chemo) have successfully treated many people with cancer.
1960 – Long-term remissions and even cures of many patients with Hodgkin disease and childhood ALL (acute lymphoblastic leukemia) treated with chemo were first reported during the 1960s.
1970s – Cures of testicular cancer were seen during the next decade. A major discovery was the advantage of using multiple chemotherapy drugs (known as combination chemotherapy) over single agents. Some types of very fast-growing leukemia and lymphoma (tumors involving the cells of the bone marrow and lymph nodes, respectively) responded very well to combination chemo, and clinical trials led to gradual improvement of the drug combinations used.
Early in the 20th century, only cancers small and localized enough to be completely removed by surgery were curable. Later, radiation was used after surgery to control small tumor growths that were not surgically removed. Finally, chemotherapy was added to destroy small tumor growths that had spread beyond the reach of the surgeon and radiotherapist.
1990 – 2001 – Discovery of targeted therapies- One approach to identify potential targets is to compare the amounts of individual proteins in cancer cells with those in normal cells. Proteins that are present in cancer cells but not normal cells or that are more abundant in cancer cells would be potential targets, especially if they are known to be involved in cell growth or survival. An example of such a differentially expressed target is the human epidermal growth factor receptor 2 protein (HER-2). HER-2 is expressed at high levels on the surface of some cancer cells. Several targeted therapies are directed against HER-2, including trastuzumab (Herceptin®), which is approved to treat certain breast and stomach cancers that overexpress HER-2.
Another approach to identify potential targets is to determine whether cancer cells produce mutant (altered) proteins that drive cancer progression. For example, the cell growth signaling protein BRAF is present in an altered form (known as BRAF V600E) in many melanomas. Vemurafenib (Zelboraf®) targets this mutant form of the BRAF protein and is approved to treat patients with inoperable or metastatic melanoma that contains this altered BRAF protein.
Researchers also look for abnormalities in chromosomes that are present in cancer cells but not in normal cells. Sometimes these chromosome abnormalities result in the creation of a fusion gene (a gene that incorporates parts of two different genes) whose product, called a fusion protein, may drive cancer development. Such fusion proteins are potential targets for targeted cancer therapies. For example, imatinib mesylate (Gleevec®) targets the BCR-ABL fusion protein, which is made from pieces of two genes that get joined together in some leukemia cells and promotes the growth of leukemic cells.
The first agent discovered was Gleevec used to treat CML.
Imatinib was invented in the late 1990s by biochemist Nicholas Lyndon then working for Ciba-Geigy (now Novartis), and its use to treat CML was driven by Brian Druker, an oncologist at the Dana-Farber Institute. The first clinical trial of Imatinib took place in 1998 and the drug received FDA approval in May 2001. Lyndon, Druker, and the other colleagues were awarded the Lasker-DeBakey Clinical Medical Research Award in 2009 for “converting a fatal cancer into a manageable condition” and the Japan Prize in 2012 for their part in “the development of a new therapeutic drug targeting cancer-specific molecules. Apart from its remarkable success in CML and GIST, Imatinib benefits various other tumors caused by Imatinib-specific abnormalities of PDGFR and c-KIT. Imatinib can be tried in Malignant melanoma having KIT aberrations.
Targeted therapies since then have developed to effectively treat Lymphomas, with very good success, these are Brentuximab, Rituximab, Ibrutinib, etc…. In addition, angiogenic blockers have shown activity in certain types of cancer with activated angiogenic pathways.
2006 – Present – Cancer vaccines and gene therapy are sometimes considered targeted therapies because they interfere with the growth of specific cancer cells. First prostate cancer vaccine had been developed since 2006. The effects are mainly preventive.
Antibodies approved by FDA for the treatment of solid and hematological tumors, e.g., rituximab (anti-CD20), cetuximab (anti-EGFR), trastuzumab (anti-HER2), bevacizumab (anti-VEGF-A), ipilimumab (anti-CTLA-4), pembrolizumab (anti-PD-1) are currently used in immunotherapy against tumor cells
2008 – Present – For the first time, scientists have looked in the cancer stem cells. The focus of many scientists has shifted from killing cancer to stem cell targeted therapies, which unfortunately to this point there has only been a failed path to treat them. Traditional therapies against cancer, chemo- and radiotherapy, have multiple limitations that lead to treatment failure and cancer recurrence. These limitations are related to systemic and local toxicity, while treatment failure and cancer relapse are due to drug resistance and self-renewal, properties of a small population of tumor cells called cancer stem cells (CSCs). These cells are involved in cancer initiation, maintenance, metastasis and recurrence. Therefore, in order to develop efficient treatments that can induce a long-lasting clinical response preventing tumor relapse it is important to develop drugs that can specifically target and eliminate CSCs.
In addition to their self-renewal and differentiation capabilities, stem cells have immunosuppressive, antitumor, and migratory properties. Because stem cells express growth factors and cytokines that regulate host innate and cellular immune pathways, they can be manipulated to both escape the host immune response and act as cellular delivery agents. Notch signaling cascade is one major pathway involved in numerous critical cellular processes, including stem cell maintenance, progenitor cell proliferation and differentiation, and determination of cell fate during embryonic development. Hadgehog, PTEN, Nf Kappa B, and Wnt targets are very attractive in cancer stem cell therapeutics, unfortunately none have a commercially available product in the market.
Although we understand a lot about the biology of cancer stem cells, there is a big challenge in creating the drugs: Drugs are not specific and might affect also healthy tissue since CSCs niche is similar and close to normal stem cell niche that can also be affected by compounds. There are also many ways by which CSCs could evade treatment. They reside is an area of low oxygen and vascularity, preventing efficient delivery of the drugs.
Cancer Research and Life Foundation has made this it’s mission to invest in discoveries of targeted cancer stem cell therapeutics, the current most challenging area of oncology. The compounds that CRL foundation is working on are not harming the normal stem cells, and therefore are considered to be superior when compared to all available products.