TARGETED THERAPIES --BIOLOGICAL AND SMALL MOLECULE DRUGS
MONOCLONAL ANTIBODIES (MABs)-
Monoclonal antibodies work in different ways and some work in more than one way. They may trigger the immune system to attack cancer cells, block molecules that stop the immune system working (checkpoint inhibitors), block signals telling cancer cells to divide or carry cancer drugs or radiation to cancer cells. Although cancer cells are abnormal, they develop from normal cells so they can be difficult for the immune system to spot. Some monoclonal antibodies simply attach themselves to cancer cells, making them easier for the cells of the immune system to find them. Antibody-dependent cell-mediated cytotoxicity (ADCC) requires antibodies to bind to target cell surfaces. Antibodies are formed of a binding region (Fab) and the Fc region that can be detected by immune system cells via their Fc surface receptors. Fc receptors are found on many immune system cells, including natural killer cells. When natural killer cells encounter antibody-coated cells, the latter's Fc regions interact with their Fc receptors, releasing perforin and granzyme B to kill the tumor cell.
Examples of monoclonal antibodies include Rituximab (against the protein CD20), Ofatumumab (against protein CD20) Alemtuzumab (against protein CD52). Antibodies under development have altered Fc regions that have higher affinity for a specific type of Fc receptor, FcγRIIIA, which can dramatically increase effectiveness.
MEDI4736 from AstraZeneca is a late-stage pipeline. The drug which has initially been trialed on lung cancer but could be extended to a whole range of tumors, and rake in annual sales of up to $5 billion.The human monoclonal antibody is directed versus programmed cell death ligand 1 (PD-L1). Signals from PD-L1 assist tumors in avoiding detection by the immune system. MEDI4736 blocks such signals, countering the tumor's immune-evading tactics. The drug compound was developed to empower a patient's immune system and attack the cancer. See: Durvalumab (MEDI4736) granted Breakthrough Therapy designation by US FDA for treatment of patients with PD-L1 positive urothelial bladder cancer.
Bentuximab vedotin- (directed against protein CD30). Bentuximab vedotin (INN, trade name Adcetris) is an antibody-drug conjugate (ADC) directed to the protein CD30, which is expressed in classical Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL). Tivozanib (AV-951) - advanced renal cell carcinoma.
Trastuzumab, sold under the brandname Herceptin among others, is a monoclonal antibody that interferes with the HER2/neu receptor. Its main use is to treat certain breast cancers.
Immune Checkpoint Inhibitors
Immune checkpoints are molecules in the immune system that either turn up a signal (co-stimulatory molecules) or turn down a signal. Many cancers protect themselves from the immune system by inhibiting the T cell signal. Since around 2010 inhibitory checkpoint molecules have been increasingly considered as new targets for cancer immunotherapies due to the effectiveness of two checkpoint inhibitor drugs that were initially indicated for advanced melanoma:. ipilimumab ( Yervoy), from Bristol-Myers Squibb, and Pembrolizumab (Keytruda), from Merck. Keytruda (Pembrolizumab, formerly MK-3475) , is a humanized antibody used in cancer immunotherapy. It targets the programmed cell death 1 (PD-1) receptor. ipilimumab,(Yervoy) which was the first FDA-approved immune checkpoint inhibitor blocks the CTLA-4 molecule on T cells, which leads to a broad enhancement of immune responses, including attacks on cancer cells. A range of newer drugs targets a different immune checkpoint protein known as PD-1. The treatments work by preventing cancer cells from attaching to the PD-1 protein on immune cells, which leads to an increased antitumor immune response and generally fewer adverse effects.
PD-1 Inhibitors --Programmed T cell death 1 (PD-1) is a trans-membrane protein found on the surface of T cells, which, when bound to programmed T cell death ligand (PD-L1) on tumor cells, results in suppression of T cell activity and reduction of T cell-mediated cytotoxicity. Thus, PD-1 and PD-L1 are immune down-regulators or immune checkpoint “off switches” .
Nivolumab- (Opdivo) is a humanized monoclonal, immunoglobulin G4 antibody to PD-1. As of April 2016, nivolumab was used as a first line treatment for inoperable or metastatic melanoma in combination with ipilimumab if the cancer does not have a mutation in BRAF (gene).
Pembrolizumab is a therapeutic antibody that blocks the inhibitory ligand of programmed cell death 1 receptor located on lymphocytes.
Durvalumab (MEDI4736), a PD-L1 antibody, made by AstraZeneca/MedImmune, is being tested in a variety of trials for patients with lung cancer.
A Phase I/II study will evaluate the safety and efficacy of MedImmune’s investigational anti-PDL1 immune checkpoint inhibitor, durvalumab (MEDI4736), in combination with mocetinostat, Mirati’s investigational spectrum-selective histone deacetylase (HDAC) inhibitor.
Atezolizumab (Genentech) – Atezolizumab (trade name Tecentriq) is a fully humanized, engineered monoclonal antibody of IgG1 isotype against the protein programmed cell death-ligand 1 (PD-L1). It is currently in clinical trials as an immunotherapy for several types of solid tumors. It is under investigation by Genentech/Roche. In April 2016 Roche announced that atezolizumab had been granted fast track status for lung cancer by the FDA. In May 2016 it was approved by the FDA for bladder cancer treatment.
Next generation checkpoint blockade for cancer immunotherapy--See Review below Reference 23-- The review presents data demonstrating the ability of A2a receptor blockade to enhance tumor vaccines, checkpoint blockade and adoptive T cell therapy.
CANCER GROWTH BLOCKERS
Protein kinase inhibitors
A protein kinase is a kinase enzyme that modifies other proteins by chemically adding phosphate groups to them (phosphorylation). Phosphorylation usually results in a functional change of the target protein (substrate) by changing enzyme activity, cellular location, or association with other proteins. The human genome contains about 500 protein kinase genes and they constitute about 2% of all human genes. Kinases are known to regulate the majority of cellular pathways, especially those involved in signal transduction. Because protein kinases have profound effects on a cell, their activity is highly regulated. Kinases are turned on or off by phosphorylation , by binding of activator proteins or inhibitor proteins, or small molecules, or by controlling their location in the cell relative to their substrates. Kinases mostly act on both serine and threonine, but tyrosine kinase acts on tyrosine only.
Vemurafenib (INN, marketed as Zelboraf) is a B-Raf enzyme inhibitor (serine/threonine-protein kinase B-Raf) developed by Plexxikon (now part of Daiichi-Sankyo) and Genentech for the treatment of late-stage melanoma. The name "vemurafenib" comes from V600E mutated BRAF inhibition.Tyrosine kinase inhibitors
Tyrosine kinase inhibitors also called TKIs. They block chemical messengers called tyrosine kinases. Tyrosine kinases help to send growth signals in cells. So blocking them stops the cell growing and dividing. Cancer growth blockers can block one type of tyrosine kinase or more than one type. TKIs that block more than one type of tyrosine kinase are called multi-TKIs.
Ponatinib - leukemia --Ponatinib (trade name Iclusig, previously AP24534) is an oral drug developed by ARIAD Pharmaceuticals for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL). It is a multi-targeted tyrosine-kinase inhibitor
Tagrisso™ (AZD9291) -Osimertinib- is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) drug developed by AstraZeneca Pharmaceuticals – for mutated EGFR cancers. See: TAGRISSO™ (AZD9291) approved by the US FDA for patients with EGFR T790M mutation-positive metastatic non-small cell lung cancer. Osimertinib has also given encouraging results in early trials as a first-line therapy.
Cabozantinib, marketed under the trade name Cabometyx among others, is a small molecule inhibitor of the tyrosine kinases c-Met and VEGFR2, and has been shown to reduce tumor growth, metastasis, and angiogenesis. It was discovered and developed by Exelixis Inc.
Acalabrutinib (rINN, ACP-196) is an experimental anti-cancer drug and a 2nd generation BTK inhibitor (bruton's Tyrosine Kinase) developed by Acerta Pharma.
It is designed to be more selective (fewer side-effects) than ibrutinib. As of 2015 it is in late stage clinical trials for relapsed chronic lymphocytic leukemia. Interim results are encouraging : 95% overall response rate. It is also in another 20 clinical trials (alone and in combination) for various cancers.
Crizotinib (PF-02341066) -Crizotinib (trade name Xalkori, Pfizer) is an anti-cancer drug acting as an ALK (anaplastic lymphoma kinase) and ROS1 (c-ros oncogene 1) inhibitor,-On March 11, 2016, the U. S. Food and Drug Administration approved crizotinib capsules (Xalkori, Pfizer, Inc.) for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are ROS1-positive. Note: Anaplastic lymphoma kinase (ALK) is also known as ALK tyrosine kinase receptor or CD246 (cluster of differentiation 246) is an enzyme that in humans is encoded by the ALK gene.
Ibrutinib (Imbruvica) On March 7, 2016 The US Food and Drug Administration (FDA) approved ibrutinib (Imbruvica, Janssen/Pharmacyclics) for first-line use in patients with chronic lymphocytic leukemia (CLL). Ibrutinib is a first-in-class oral, covalent inhibitor of Bruton's tyrosine kinase. The drug has already been approved for use in patients with pretreated CLL, and in CLL patients with the del17p mutation (including as initial treatment).
The Janus kinases (JAKs) and signal transducer and activator of transcription (STAT) proteins, particularly STAT3, are among the most promising new targets for cancer therapy. In addition to interleukin-6 (IL-6) and its family members, multiple pathways, including G-protein-coupled receptors (GPCRs), Toll-like receptors (TLRs) and microRNAs were recently identified to regulate JAK–STAT signalling in cancer. Well known for its role in tumour cell proliferation, survival, invasion and immunosuppression, JAK–STAT3 signalling also promotes cancer through inflammation, obesity, stem cells and the pre-metastatic niche. In addition to its established role as a transcription factor in cancer, STAT3 regulates mitochondrion functions, as well as gene expression through epigenetic mechanisms. Newly identified regulators and functions of JAK–STAT3 in tumours are important targets for potential therapeutic strategies in the treatment of cancer.Proteasome Inhibitors
Proteasome inhibitors are drugs that block the action of proteasomes, cellular complexes that break down proteins. Proteasome inihibitors cause a buildup in unwanted proteins in the cell, which makes the cancer cells die.
Bortezomib.(Velcade).Multiple mechanisms are likely to be involved, but proteasome inhibition may prevent degradation of pro-apoptotic factors such as the p53 protein, permitting activation of programmed cell death in neoplastic cells dependent upon suppression of pro-apoptotic pathways.
Ixazomib (trade name Ninlaro) is the first orally-available proteasome inhibitor approved by the FDA on November 20, 2015 for use in combination with lenalidomide and dexamethasone for the treatment of multiple myeloma after at least one prior therapy.
Carfilzomib (Kyprolis) FDA Approves New Kyprolis® (Carfilzomib) Combination Therapy For The Treatment Of Patients With Relapsed Or Refractory Multiple Myelom from Amgen -- January 21, 2016. Carfilzomib (marketed under the trade name Kyprolis, developed by Onyx Pharmaceuticals) is an anti-cancer drug acting as a selective proteasome inhibitor .
Mammalian target of rapamycin (mTOR) is a serine/threonine kinase, which belongs to phosphatidylinositol-3 kinase (PI3K) related kinases (PIKKs) family. It regulates cellular metabolism, growth, and proliferation, and therefore is a target for the development of a number of mTOR inhibitors. See PI3K/mTOR Dual Inhibitor-- for mechanism of action of LY3023414. The PI3K/mTOR (phosphoinositide 3-kinase/mammalian target of rapamycin) pathway is stimulated by a variety of growth factors and their receptors and regulates cell metabolism, cell growth, cell survival, cell proliferation, cell motility, and angiogenesis. The PI3K/AKT/mTOR pathway is thought to be one of the most frequently mutated pathways in cancer,1,2 leading to cancer progression and resistance to existing treatments.2,3 kinase/mammalian target of rapamycin) pathway is stimulated by a variety of growth factors and their receptors and regulates cell metabolism, cell growth, cell survival, cell proliferation, cell motility, and angiogenesis. The PI3K/AKT/mTOR pathway is thought to be one of the most frequently mutated pathways in cancer, leading to cancer progression and resistance to existing treatments. LY3023414 is a small molecule that has been shown in vitro to be a selective ATP-competitive inhibitor of PI3Kα and mTOR, DNA-PK, and other class I PI3K family members. LY3023414 is being investigated in phase I clinical trials and in clinical trials in patients with non-small cell lung cancer and prostate cancer.
Proapoptotic Small Molecule Drugs
Bcl-2 inhibitors/pathways--Targeting Mitochondrial Apoptotic Pathways in Cancer Therapy--Inhibition of pro-survival proteins of the BCL family is a promising anti-cancer strategy.
Bcl-2 (B-cell lymphoma 2) is a regulator protein that regulate cell death (apoptosis), by either inducing (pro-apoptotic) or inhibiting (anti-apoptotic) apoptosis. Bcl-2 is specifically considered an important anti-apoptotic protein and is thus classified as an oncogene.
Venetoclax (AbbVie/Genentech) –is an oral treatment for certain patients with chronic lymphocytic leukemia. Venetoclax acts as a Bcl-2 inhibitor. It blocks the anti-apoptotic B-cell lymphoma-2 (Bcl-2) protein, leading to programmed cell death of CLL cells. Bcl-2 (B-cell lymphoma 2). Bcl-2 is specifically considered an important anti-apoptotic protein and is thus classified as an oncogene. On April 11, 2016, the FDA approved venetoclax for use in patients with CLL who have 17p deletion (deletion located on the chromosome 17 short arm) and who have been treated with at least one prior therapy. See more Bcl-2 Inhibitors.PI3K inhibitor
A phosphoinositide 3-kinase inhibitor (PI3K inhibitor) is a class of drug that functions by inhibiting one or more of the phosphoinositide 3-kinase enzymes, which are part of the PI3K/AKT/mTOR pathway, an important signalling pathway for many cellular functions such as growth control, metabolism and translation. See PI3K inhibitors.Histone deacetylase inhibitors
Histone deacetylases are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on a histone, allowing the histones to wrap the DNA more tightly. Histone deacetylase inhibitors removes acyl groups from histones which inhibit cancer cells from growing and dividing.
Entinostat (Syndax Pharmaceuticals) – an oral medication for certain types of breast cancer. Entinostat, also known as SNDX-275 and MS-275, is a benzamide histone deacetylase inhibitor undergoing clinical trials for treatment of various cancers.
Hedgehog Signaling Pathway
The Hh signaling pathway has recently been recognized to be one of the most important signaling pathways and a therapeutic target in cancer. In adults, mutation or deregulation of this pathway plays a key role in both proliferation and differentiation leading to tumorigenesis or tumor growth acceleration in a wide variety of tissues.
GDC-0449 (vismodegib) - Vismodegib (trade name Erivedge) is a drug for the treatment of basal-cell carcinoma (BCC). Vismodeglb acts as a cyclopamine-competitive antagonist of the smoothened receptor (SMO) which is part of the hedgehog signaling pathway. The approval of vismodegib on January 30, 2012, represents the first Hedgehog signaling pathway targeting agent to gain U.S. Food and Drug Administration (FDA) approval.
DRUGS THAT BLOCK BLOOD VESSEL GROWTH( angiogenesis inhibitors )-- There are different types of drugs that block blood vessel growth, including: Drugs that block blood vessel growth factor, drugs that block signalling within the cell, drugs that affect signals between cells and drugs that block blood vessel growth factor. Some drugs block vascular endothelial growth factor (VEGF) from attaching to the receptors on the cells that line the blood vessels. This stops the blood vessels from growing. A drug that blocks VEGF is bevacizumab (Avastin). It is also a monoclonal antibody. See Reference 15. The FDA has approved several other drugs that have antiangiogenic activity, including sorafenib (Nexavar®), sunitinib (Sutent®), pazopanib (Votrient®), and everolimus (Afinitor®).
Tumour vascular-disrupting agents
Tumour vascular-disrupting agents target established tumour vasculature and might be more effective against large tumour masses. Combretastatin A4 phosphate is one of drug in clinical trial development. Combretastatins are tubulin depolymerising drugs that selectively disrupt the tumour endothelial cytoskeleton and cause rapid tumour vascular shutdown and necrosis.
Interferon and Interleukin 2 (immunotherapy)--Interferon and interleukin can boost the immune system, so doctors sometimes use man made versions to treat cancer. Because of the way it works, doctors sometimes call this type of treatment immunotherapy. (Reference 16)
BOOSTING THE IMMUNE SYSTEM
In November 2013, the FDA approved obinutuzumab, used in combination with the standard CLL (Chronic lymphocytic leukaemia) chemotherapy drug chlorambucil, for previously untreated CLL. Obinutuzumab is an immunotherapy drug that works by helping certain cells in the immune system attack cancer cells. The approval was based on a clinical trial in 365 patients that showed that the combination of obinutuzumab and chlorambucil was more effective than chlorambucil alone (which has been a standard treatment for CLL for decades, more recently in combination with rituximab). This study focused on patients with coexisting medical conditions that ruled out standard chemotherapy and immunotherapy approaches because of safety concerns. The new treatment more than doubled the average time to disease progression, from 11 to 23 months.
IMMUNOTHERAPY USING VIRUSES
PROSTVAC (rilimogene galvacirepvec/rilimogene glafolivec) that utilizes recombinant poxviruses to express PSA. It is a cancer immunotherapy candidate in clinical development by Bavarian Nordic for the treatment of metastatic castration-resistant prostate cancer (mCRPC). PROSTVAC is designed to enable the immune system to recognize and attack prostate cancer cells by triggering a specific and targeted T cell immune response to cancer cells that express the tumor-associated antigen prostate-specific antigen (PSA). PROSTVAC utilizes recombinant poxviruses to express PSA, along with 3 immune-enhancing costimulatory molecules collectively designated as TRICOM (LFA-3, ICAM-1, and B7.1).PROSTVAC immunotherapy is intended to trigger a specific and targeted immune response against prostate cancer cells and tissue by using virus-based immunotherapies that carry the tumor-associated antigen PSA (prostate-specific antigen) along with 3 natural human immune-enhancing costimulatory molecules collectively designated as TRICOM (LFA-3, ICAM-1, and B7.1). The median overall survival was 31.3 months. It was 37.2 months for patients who got a 10 mg/kg dose, and 20% of patients in this group remain alive at the 80-month mark.. See 2015 Phase I results.
Talimogene laherparepvec ( --often simply called "T-VEC" is a cancer-killing (oncolytic) virus studied for the treatment of melanoma and other advanced cancers. The drug was developed by BioVex, Inc. under the name OncoVEXGM-CSF. It was acquired by Amgen in 2011. With the announcement of positive results in March 2013, T-VEC became the first oncolytic virus to be demonstrated effective in a Phase III clinical trial.In October 2015, the US FDA approved T-VEC, under the brand name Imlygic, for the treatment of melanoma in patients with inoperable tumors.
TARGETING CANCER STEM CELLS AND METASTASIS
Salinomycin has been shown by Piyush Gupta et al. of the Massachusetts Institute of Technology and the Broad Institute to kill breast cancer stem cells in mice at least 100 times more effectively than the anti-cancer drug paclitaxel. The study screened 16,000 different chemical compounds and found that only a small subset, including salinomycin and etoposide, targeted cancer stem cells responsible for metastasis and relapse.
The mechanism of action by which salinomycin kills cancer stem cells specifically remains unknown, but is thought to be due to its action as a potassium ionophore due to the detection of nigericin in the same compound screen. Studies performed in 2011 showed that salinomycin could induce apoptosis of human cancer cells. Promising results from a few clinical pilote studies reveal that salinomycin is able to effectively eliminate CSCs and to induce partial clinical regression of heavily pretreated and therapy-resistant cancers. The ability of salinomycin to kill both CSCs and therapy-resistant cancer cells may define the compound as a novel and an effective anticancer drug.
Targeting Melonoma Metastasis --"We found that even before the cancer itself invades the dermis, it sends out tiny vesicles containing molecules of microRNA," said Carmit Levy: See Ref 28 and 29. The researchers found two chemicals that would block the vesicles : one (SB202190) inhibits the delivery of the vesicles from the melanoma tumor to the dermis; and the other (U0126) prevents the morphological changes in the dermis even after the arrival of the vesicles. Both substances were tested successfully in the lab, and may serve as promising candidates for future drugs. In addition, the changes in the dermis, as well as the vesicles themselves, can be used as powerful indicators for early diagnosis of melanoma. Note: SB202190 (FHPI) is a potent p38 MAPK inhibitor targeting p38α/β with IC50 and U0126 is a highly selective inhibitor of both MEK1 and MEK2, a type of MAPK/ERK kinase.
Cancer Stemness Signaling Pathways -- see see 2016 CSC Conference -- Cancer Stem Cell Conference
Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update --See reference 27.
Demcizumab --Celgene's partnership with OncoMed Pharmaceuticals. OncoMed is developing drugs that target cancer stem cells, or CSCs, which are typically impervious to chemotherapy and radiation therapy. It's believed by researchers that CSCs are also what's responsible for cancer recurrence and metastasis.
OncoMed's lead product is demcizumab, a monoclonal antibody that targets DLL4, an activator notch that's important for the development of cancer. Demcizumab blocks Delta-like ligand 4 (DLL4), a ligand of Notch receptors. Notch signaling has been implicated as a key signaling pathway in cancer stem cells. By treating patients with a combination of Demcizumab and a cytotoxic chemotherapy, it is hoped that a more durable anti-tumor response can be achieved than with chemotherapy alone.
INTEGRINS AND METASTASIS
Beta 1-integrin–c-Met cooperation reveals an inside-in survival signalling on autophagy-related endomembranes --Receptor tyrosine kinases (RTKs) and integrins cooperate to stimulate cell migration and tumour metastasis.
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.
DRUGS TO TARGET THE WARBURG HYPOTHESIS
Malignant cells exhibit aerobic glycolysis (the Warburg effect) and become dependent on de novo lipogenesis, which sustains rapid proliferation and resistance to cellular stress. The nuclear receptor liver-X-receptor (LXR) directly regulates expression of key glycolytic and lipogenic genes. To disrupt these oncogenic metabolism pathways, we designed an LXR inverse agonist SR9243 that induces LXR-corepressor interaction. In cancer cells, SR9243 significantly inhibited the Warburg effect and lipogenesis by reducing glycolytic and lipogenic gene expression. SR9243 induced apoptosis in tumors without inducing weight loss, hepatotoxicity, or inflammation. Our results suggest that LXR inverse agonists may be an effective cancer treatment approach.
Novel drugs that target the metabolic reprogramming in renal cell cancer-- Preclinical research indicates that mutations in VHL, FBP1, and the PI3K-AKT-mTOR pathway drives aerobic glycolysis through transcriptional activation of the hypoxia-inducible factors (HIF).
Potential cancer drug DCA tested in early trials -- Reference 12---The controversial drug DCA (dichloroacetate) is in the headlines again, after researchers in Canada carried out a small-scale clinical trial of the drug in five patients with advanced brain tumours. An interesting aspect of DCA is that it's an inexpensive, non-patentable molecule, which makes it of minimal value to pharmaceutical companies that profit by patenting expensive new drugs. DCA however seems to have major side-effects when not properly managed.
READINGS AND REFERENCES:
3- Innovation Tops Current Trends in the 2016 Oncology Drug Pipeline -- "Noteworthy cancer treatments include Darzalex, Empliciti, Farydak, and Ninlaro, to treat patients with multiple myeloma…, Alecensa and Tagrisso, to treat certain patients with non-small cell lung cancer, Cotellic, to treat certain patients with metastatic melanoma…, Lonsurf, for the treatment of certain patients with metastatic colorectal cancer