Worldwide, cancer ranks the second highest cause for deaths. Over the last four decades, the blueprint of cancer treatment has changed drastically. Previously; surgery, chemotherapy and radiotherapy were the only effective ways to fight against the cancer. In recent times, the era of designing cancer therapy focusing on the molecular features and genetic diversity of the tumours is emerging.

Newer tools and techniques available for early detection of cancer have increased access to healthcare whereas new medicines and novel therapies have contributed to significant improvement in the outcome as well as survival of the patients. This blog highlights some of the remarkable landmarks/recent advancements and future directions in cancer therapy:

Nanomedicines

There are numerous drawbacks associated with conventional cancer treatment, such as high toxicity, high doses, solubility and stability issues of the chemotherapeutic agents etc., the biggest being the inability to deliver the drug in adequate quantity to the tumour site without undesirable side effects. Nanotechnology, which deals with nanosized materials, has emerged as a promising technology which has enabled the development of novel therapies and devices for improved diagnosis and treatment of cancer.

Nanomedicines have been developed which specifically target the cancer cells, improve the pharmacokinetics, enhance efficacy and reduce systemic toxicity of cancer therapeutics. It has also made possible the delivery of various diagnostic and therapeutic agents including chemotherapeutic drugs, proteins, peptides, imaging and diagnostic agents, aptamers, antibodies and genes.

Nanotherapeutics also have the advantage of prolonged circulation time along with passive targeting by preferential accumulation into the tumours due the enhanced permeation and retention (EPR) effect, where the nanosized particles can easily permeate the leaky vasculature of the tumor cells and are retained within the tumor because of its poor lymphatic drainage.

Further, active targeting is also feasible and enhances the specificity of the nanotherapeutics by targeting the tumor microenvironment and also the various proteins and receptors which are overexpressed on the tumours. Since 1995, 50 nanomedicines have received FDA approval and are currently available for clinical use. Many nanoplatforms like liposomes, lipid nanoparticles, dendrimers, micelles, gold nanoparticle, nanocapsules, nanorods etc. are being used in diagnosis and treatment of cancer.

Liposomes, a colloidal drug delivery system made up from phospholipids are one of the most approved nanomedicines for anticancer therapy. PEGylated liposomes such as Doxil (Doxorubicin liposomes), DaunoXome (Daunorubicin liposomes), Myocet (liposomal Doxorubicin), DepoCyt (liposomal Cytarabine), Onivyde (liposomal Irinotecan), Mepact (liposomal Mifamurtide), and Marquibo (liposomal Vincristine) are approved by FDA for cancer treatment. Some nanomedicines are fabricated by conjugation or adsorption or complex formation of a chemotherapeutic agents; either with proteins or polymers.

Protein nanoparticles such as Abraxane (albumin bound Paclitaxel), Ontak (Denileukin diftitox, an Interleukin combined with Diphtheria toxin) and polymeric nanoparticles such as Eligard (Leuprolide acetate bound to a DL-lactide-co-glycolide polymer) are some examples of FDA approved nanomedicines. Nanotheranostics combine the benefits of diagnosis using imaging agents and biomarkers in addition to delivery of therapeutic agents. NanoTherm (MagForce Nanotechnologies AG, Berlin) which constitutes magnetic nanoparticle received approval in Europe for focussed thermal ablation of tumours.

Targeted Therapy

For years, chemotherapeutic agents have been used for cancer treatment and are still regarded as a first choice for cancer therapy. Recently “targeted anticancer therapy” has dramatically improved the clinical outcome of cancer treatment. First step in development of targeted therapy is identification of the “target”, which plays a key role in cancer cell growth, proliferation, progression and survival. It consists of drugs or other anti-cancer agents which are capable of blocking growth and spreading of cancer cells by interacting with specific molecular targets responsible for growth, progression and spread of cancer cells. These therapies are also known as molecularly targeted therapy/drugs, precision medicines etc.

• Hormonal therapy: Hormones are chemical messengers produced by glands (such as ovaries, testicles, pancreas etc.) which when released into the bloodstream circulate to various tissues and affect processes such as growth, development and metabolic functions. Hormones can either help some type of cancers to grow (breast cancer, prostate cancer) or in some cases can destroy the cancer cells. While giving hormonal therapy, hormone receptor test is done in which amount of hormone receptors present on cancer tissue is measured. If the test is positive then the hormones are considered responsible for supporting the growth of tumours. Then hormonal therapy is given to block the cancer cells supporting hormones or to inhibit them from binding to cancer cells. FDA has recently approved Apalutamide (ERLEADA) for metastatic prostate cancer, Olaparib (LYNPARZ), Abemaciclib (VERZENIO) to treat adult patients who have hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer.
• Signal transduction inhibitors: Signal transduction inhibitors are the inhibitors which block passing of signals from one molecule to another inside a cell. This results in alteration of cell functions including cell-division and cell death. Tyrosine kinase inhibitors such as Imatinib (GLEEVEC), Erlotinib (TARCEVA; block epidermal growth factor receptors (EGFR)); mTOR inhibitors such as Temsirolimus (TORISEL), proteasome inhibitor such as Bortezomib (VELCADE) are some examples of FDA approved signal transduction inhibitors.
• Apoptosis inducers: Apoptosis, also known as “programmed cell death” is a process which is responsible for controlled cell death and helps the body to get rid of abnormal or unneeded cells. A major hallmark of cancer is that cancer cells are capable of evading apoptosis. There are several molecules which are being investigated as apoptosis inhibitors. One FDA approved drug, 6,8-Bis(benzylthio)-octanoic acid also known as DEMIVISTAT, which acts by targeting enzymes involved in cancer cell energy metabolism located in the mitochondria of cancer cells has been granted orphan drug status by the US FDA for pancreatic cancer.
• Angiogenesis inhibitors: Angiogenesis involves formation of new blood vessels, through migration, growth and differentiation of endothelial cells present inside the walls of blood vessels. Angiogenesis plays an important role in the tumour biology because tumour needs blood supply and cancer cells are capable for inducing angiogenesis by triggering signals to ensure supply of nutrients and oxygen to tumours. Angiogenesis inhibitors block the growth of blood vessels that are supporting tumour growth instead of blocking the tumour cells themselves. Some of the FDA approved angiogenesis inhibitors are Lenvatinib (LENVIMA), Lenalidomide (REVLIMID), Everolimus (AFINITOR), Bevacizumab (AVASTIN), Thalidomide (SYNOVIR,THALOMID) etc.

Immunotherapy

Immunotherapy, as the name suggests is based on the immune response of the body which are utilised to design the cancer therapy. This therapy helps the body to detect and attack cancer cells in order to kill them; in a similar way it detects and kills bacteria and viruses. Experts believe that, field of immunotherapy is really promising and can provide radical ways to treat various cancers. This is evident from the fact that many immunotherapy approaches are being investigated and are showing immense potential in cancer treatment. Immunotherapy is considered as a part of targeted therapy.

• Monoclonal antibodies: Our body’s defence to any disease or infection is based on antigen-antibody response. Antibodies are specific proteins produced by the immune system which attach to antigens present on the cells. This acts as a detection step of infection, wherein after attachment the antibodies send signal to the immune system to attack the infected cells. Monoclonal antibodies (popularly known as mAbs) are lab-engineered antibodies that are all clones of a unique parent cell. mAbs are designed to attach to specific antigens present on cancer cells so that they are recognised by the immune cells and thereby destroyed. They are used to treat various cancers either alone or in combination with other chemotherapeutic agents. There are several FDA approved mAbs, Daratumumab (DARZALEX), Alemtuzumab (CAMPATH, LEMTRADA), Ofatumumab (ARZERRA), Bevacizumab (AVASTIN) etc. for treatment of various cancers.
• Checkpoint inhibitors: Our immune system (especially T cells) can attack cancer cells but some proteins produced by some cancer cells act as “check-point” for cancer cells and thus prevent immune cells from attacking the cancer cells. Checkpoint inhibitors are the inhibitors which block such proteins, thus facilitating attacking and killing of cancer cells by the immune system. Checkpoint inhibitors are regarded as a type of mAbs or targeted therapy. There are 3 major types of checkpoint proteins 1. CTLA-4 (cytotoxic T lymphocyte associated protein-4) 2. PD-1 (programmed cell death protein-1) 3.PD-L1 (programmed death ligand-1). Out of these CTLA-4 and PD-1 are found present on T-cells while PD-L1 is specific to cancer cells. Recently, FDA has approved 5 checkpoint inhibitors and till date, a total of 7 checkpoint inhibitors have been approved. Some of the examples of approved checkpoint inhibitors are, Nivolumab (OPDIVO); Pembrolizumab (KEYTRUDA), Ipilimumab (YERVOY), Atezolizumab (TECENTRIQ) etc.
• CAR T-cell therapy: Chimeric Antigen Receptor T-cell (CAR-T) therapy, as the name suggests is based on T cell, and is often regarded as “Live cell therapy”. In this therapy, T-cells which form a backbone of immune system; are isolated from patient blood. These cells are engineered by inserting genes to produce special receptors known as chimeric antigen receptors (CAR’s) on their surface. These modified T-cells known as CAR-Ts are allowed to multiply into millions of cells in the laboratory and after one or two chemotherapy cycles termed as lymphodepletion, these CAR-Ts are administered in patients’ blood via infusion. Inside the patient’s system, the cells further multiply and lead to destruction of the tumor cells by events initiated by the attachment of CAR’s to specific proteins or antigens on the tumor cells. CAR-T therapy has shown remarkable results and evolution, some of the FDA approved CAR-T therapy are Tisagenlecleucel (KYMRIAH), Axicabtagene ciloleucel (YESCARTA) and Tocilizumab (ACTEMRA).

Virotherapy

Virotherapy is a new dimension in the cancer treatment, which involves use of replication competent viruses to find and destroy cancer cells without harming normal cells. Virotherapy includes oncolytic virotherapy, viral immunotherapy and viral vectors. In Oncolytic virotherapy, virus is used to infect the cancer cells through binding to surface receptors on cancer cells or plasma membrane fusion which then initiates a lytic cycle leading to destruction of the cancer cells with no harm towards normal cells.

Viral immunotherapy and viral vectors are also known as viral gene therapy, in which a virus or lab-engineered virus is used to deliver antigen to stimulate the immune system or proteins which can alter cancer cell genes. Though there are numerous virotherapeutic approaches are in research and clinical trials, there is only one FDA approved oncolytic virus; talimogene laherparepvec (Imlygic®), or T-VEC which is used in treatment of melanoma.

Concluding remarks: Increased understanding of tumour biology, advancements in nanotechnology and development of chemotherapeutic agents has led to develop a plethora of cancer treatments which has helped in better diagnosis, treatment and prevention of cancer.

Anticancer therapies are being developed by exploiting distinguished properties of cancer cells which are not observed in normal cells. In future; better understanding of cancer proteins, markers, tumour biology and genes can mark the beginning of tailor-made treatments being provided to each individual cancer patient.

References:

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