Drugs used in oncology

Drugs used in oncology

Malignant disorders, also called cancers, are an important group of disorders. They constitute a substantial proportion of non-communicable diseases and affect all regions of the world. Cancers, such as of prostate, lung, colon and breast are an important cause of high mortality despite heavy cost. Although with advancement in medical sciences, better treatment options are being devised leading to improved survival rates among patients but their morbidity and mortality still remains high. There are a number of challenges while treating cancers, such as, disease stage at the time of diagnosis, disease behavior, patient characteristics, limited treatment options, expensive treatment, resistance to treatment, potentially lethal adverse effects and disease recurrence. Topics in this module include the drugs used in treating cancer including their mechanisms of action and adverse effects, and general principles of their use.

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Introduction to antineoplastics

Cancer chemotherapy has changed dramatically and advances in our understanding of cancer biology is facilitating development of drugs that produce cures.

Chemotherapy may be indicated as a primary treatment or as adjuvant or neoadjuvant therapy. The former is used when there are no other effective treatment approaches. Adjuvant therapy is used to eradicate micrometastatic disease following localized treatments such as surgery or radiation or both. Neoadjuvant chemotherapy is used to make other treatment modalities more effective by reducing tumor burden and to destroy micrometastases.

Despite the high cure rates of previously lethal cancers, the use of these drugs is associated with significant harmful effects. Thus, a thorough understanding of the pharmacology of the antineoplastics is important for their safe and effective use in clinical practice.

The compounds used in cancer chemotherapy are varied in structure and mechanism of action, including alkylating agents; antimetabolite analogs; natural products; hormones and hormone antagonists; and a variety of agents directed at specific molecular targets.

  • Alkylating drugs and platinum compounds: These drugs are the classical cytotoxic drugs which chemically bind with macromolecules such as DNA and disrupt cell dynamics, growth and differentiation.
  • Anthracyclines: These drugs disrupt DNA replication and transcription by DNA intercalation, a type of physical binding. Ultimately, they shift the balance in favor of cancer cell apoptosis.
  • Antimetabolites: These drugs disrupt the metabolism inside the cells by inhibiting folate metabolism and/or DNA synthesis.
  • Topoisomerase inhibitors: inhibit the release of supercoils during DNA replication and transcription and thus disrupt DNA dynamics.
  • Antimitotic Drugs (Vinca alkaloids and Taxanes): Inhibit the dynamic instability of microtubules and thus arrests the cell cycle in mitosis.
  • Protein kinase inhibitors and Antibodies: These are relatively new group of drugs which target specific growth receptors and thus help control cell growth and differentiation.

The biological targets of anticancer therapy are present throughout the cell, from cell membrane to nucleus. The cell cycle specificity is an important attribute and it determines the selection of drug regimen, among other factors. Likewise, ability to eradicate cancer cells can be judged with log-kill hypothesis.

Dr Nasir Afsar

This 42-minute video introduces the concept of chemotherapy for cancer. In addition to a short description of the log kill hypothesis, the mechanisms of action of the main classes of antineoplastic drugs are described. These include the cytotoxic drugs (e.g. alkylating agents), hormones, and immunoglobulins and tyrosine kinase inhibitors. The video concludes with a general overview of the general principles of chemotherapy and adverse effects. This video would be appropriate for learners as they begin their study of antineoplastic drugs. Presentation created and contributed by Dr Nasir Afsad, Alfaisal University College of Medicine, Riyadh, Saudi Arabia.

Average: 3.9 (21 votes)

Alkylating Agents: Nitrogen mustard derivatives

Several alkylating agents are used in clinical practice. They all share the same mechanism of action; they introduce alkyl groups into nucleophilic sites on other molecules, DNA being the principal target in cancers.  Alkylating agents can be subdivided into chemical classes, one of which is the nitrogen mustard derivatives.

Nitrogen mustard derivatives include cyclophosphamide, melphalan, chlorambucil, and others. They are not derived from mustard plants but they do have an interesting and grim history. These compounds were initially developed for trench warfare in World War I ('mustard gases') and they were dropped on enemy troops from planes. High doses were quickly lethal, but it was noticed that individuals who were exposed to lower doses downwind from the battlefield, developed severe low white blood counts. Two American pharmacologists, Louis Goodman and Alfred Gilman, decided to change the agents from gas to liquid formulations and administered them intravenously into a patient with malignant lymphoma. They found that the cancer cells disappeared within two weeks. Unfortunately, the cancer returned later and the patient died, but this was the first step in cancer chemotherapy. This was the birth of modern chemotherapy and a positive outcome of chemical warfare. Cyclophosphamide was identified through this research process, and it has become one of the most commonly used agents in a range of chemotherapy regimens. The nitrogen group in the molecule is extremely reactive and the majority of the cytotoxic effects come from the irreversible binding of these nitrogens to the DNA molecule at the N-7 position on the guanine base- this is the 'alkylation' reaction. This insertion of a chemical along the DNA molecule disrupts DNA replication and increases the likelihood of DNA breaks. In addition, the drugs can form cross-links between two DNA strands, further adding to the inability of the cell to repair or use the damaged DNA. So, all DNA is susceptible to these agents, but cells that are rapidly dividing and growing (e.g., cancer cells) are more susceptible than non-cancer somatic cells. Cells that have rapid turnover (skin, hair, and gastric mucosa) are inherently more susceptible to cancer chemotherapy, and collateral damage to these tissues manifests as skin hypersensitivities and rashes, alopecia, and GI upset/nausea and vomiting. 

Cyclophosphamide is discussed here, as the prototype alkylating agent. It is used for a variety of hematologic and solid organ tumors. Cyclophosphamide can be given orally without causing significant damage to the gastrointestinal epithelium because it is metabolized and activated in the liver.The toxicity profile includes a dose-limiting myelosuppression, delayed and acute nausea and vomiting, SIADH (syndrome of inappropriate antidiuretic hormone secretion), alopecia, and hemorrhagic cystitis. Hemorrhagic cystitis is rarely observed in practice since we know how to prevent it. Acrolein is the cyclophosphamide metabolite that is toxic to the urinary bladder. Its accumulation in the bladder results in severe damage to the bladder mucosa and presents with pain and discomfort, as well as blood in urine. To prevent this toxicity, vigorous hydration before administration of cyclophosphamide and ensuring urine output is over 100 mL/hour will assist in preventing hemorrhagic cystitis. Co-administration of MESNA (mercapto-ethane sulfonates) also helps to prevent hemorrhagic cystitis. MESNA acts as an acrolein scavenger, by binding to acrolein via its reactive sulfhydryl group. This reaction generates a stable, non-toxic byproduct. Ifosfamide (a second-generation agent) is more toxic than cyclophosphamide and must always be given with MESNA. Usually, vigorous hydration is sufficient to combat hemorrhagic cystitis with cyclophosphamide; however, MESNA may be given with higher doses of cyclophosphamide and especially with ifosfamide. N-acetyl-cysteine, a thiol agent, has also been used to reduce these side effects.

Other alkylating agents that are used in many chemotherapy regimens include the platinum-containing agents carboplatin and cisplatin. Like nitrogen mustards, these platinum compounds disrupt DNA replication and interfere with cancer cell growth.

Michael Bradaric (Rush Medical College)

This is a 35 minute video that describes alkylating agents that are used as cancer chemotherapy. It has a lot of detail, including information regarding their development, chemistry (and synthesis), structure-activity relationships, mechanism of action and pharmacology. Some of the most widely used drugs are mentioned specifically.

It was produced by YR Pharma Tube.

Suitable for intermediate level learners.

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Antimetabolites

Antimetabolite drugs interfere with the synthesis of the building blocks of DNA (purine and pyrimidine bases or their corresponding nucleosides), disrupting DNA (and for some drugs RNA) synthesis and replication. Most of these drugs are structural analogues of the endogenous molecules or folate cofactors crucial for purine and pyrimidine biosynthesis. Antimetabolite class drugs principally target the de novo nucleotide synthetic pathways crucial for supplying the large nucleotide pools required by highly proliferating cancer cells. Antimetabolite drugs can be categorised into three primary subgroups:

  1. folic acid antagonists
  2. purine analogues
  3. pyrimidine analogues.

1. Folic acid antagonists

Methotrexate is both a chemotherapeutic agent and a general immunosuppressant for systemic inflammatory diseases such as rheumatoid arthritis and psoriasis. Often used to counteract systemic inflammation in rheumatic conditions, such drugs are known as disease-modifying antirheumatic drugs (DMARDs), with methotrexate emerging as a first-line DMARD.

Methotrexate inhibits dihydrofolate reductase (DHFR), the primary enzyme responsible for converting folic acid to its more physiologically active reduced form folate-  an essential step in DNA synthesis. Consequently methotrexate treatment results in a build-up of inactive folates. Despite resembling folate, methotrexate can induce a range of toxicities, including myelosuppression (dose-limiting), mucositis, hepatotoxicity, nephrotoxicity and neurotoxicity. To mitigate nephrotoxicity, vigilantly maintaining hydration and alkalinising urine (achieving pH >7) are recommended. Additionally, patients taking methotrexate should avoid concomitant use of other nephrotoxic drugs and those that may interact with methotrexate. For example, certain weak acids like non-steroidal anti-inflammatory drugs (NSAIDs) and penicillin compounds may precipitate methotrexate. The fixed-dose antibacterial medication trimethoprim/sulfamethoxazole may compete for reabsorption in renal tubules, and proton pump inhibitors such as omeprazole may inhibit the clearance of methotrexate, thereby exacerbating side effects. The risk of methotrexate-induced adverse effects escalates with dosage. Therefore, in the case of high-dose methotrexate administration (>1000 mg/m2), supplementation with leucovorin (folinic acid; a reduced form of folate) is advised. This approach, known as a 'leucovorin rescue' supplies essential folate in a usable form to combat the myelosuppression and gastrointestinal toxicity observed in patients treated with high-dose methotrexate. Leucovorin counters the folate depletion caused by methotrexate, primarily benefiting the healthy (non-cancer) cells. Administered 12-24 hours post methotrexate infusion, leucovorin treatment continues until methotrexate is eliminated from the body. Alternatively, high-dose folic acid supplementation can achieve the same benefit.

It is hypothesised that cancer cells, likely exhibiting elevated active dihydrofolate reductase levels, preferentially bind methotrexate, partially sparing its impact on normal cells. As methotrexate can accumulate in the interstitial space between cells, its levels are routinely monitored. If significant accumulation transpires, glucarpidase (a recombinant bacterial enzyme that breaks down methotrexate into inactive metabolites) can be administered to quickly lower heightened methotrexate levels in patients suffering from severe toxicity due to the drug.

2. Purine analogues

6-mercaptopurine (6-MP) is an active metabolite derived from the prodrug, azathioprine. It functions by incorporating into DNA in place of the natural purine bases, thereby interfering with DNA synthesis and leading to miscoding in both DNA and RNA. Consequently, DNA replication is impaired and the proliferation of cancer cells is hindered. 6-MP is primarily indicated for acute lymphoid leukaemia (ALL). However, the use of 6-MP can result in common adverse reactions such as myelosuppression (suppression of bone marrow function leading to reduced blood cell production), mucositis (inflammation of the mucous membranes), nausea/vomiting and hepatotoxicity (liver toxicity). Furthermore, it is important to be aware of several significant drug-drug interactions that may arise from clinical use. For instance, co-administration of allopurinol can elevate the concentration of 6-MP, potentially increasing its toxicity.

3. Pyrimidine analogues

5-fluorouracil (5-FU) is the most commonly used pyrimidine analogue in clinical practice. It acts as an analogue of pyrimidines, specifically thymine and cytosine, and exterts its mechanism of action by inhibiting the activity of thymidylate synthase (TYMS). TYMS plays a crucial role in the rate-limiting step of thymidine generation, which is essential for DNA synthesis and cellular proliferation. Upon administration 5-FU is metabolised into its active form, 5-fluorouracil triphosphate, which is incorporated into RNA.

The primary therapeutic use of 5-FU is in the treatment of various cancers, including colon, pancreatic, and head and neck cancers, as well as certain haematological malignancies. However, the toxicities associated with 5-FU can vary depending on the method of administration. Bolus intravenous infusions are linked to myelosuppression, while continuous intravenous infusions can lead to mucositis, diarrhoea, and hand-foot syndrome. Other reported adverse effects include phototoxicity, cardiotoxicity, skin manifestations and rashes, alopecia, and ocular toxicity.

Folinic acid (leucovorin) is often administered in combination with 5-FU to enhance the drug's effectiveness. Leucovorin increases the stability of 5-FU's binding to thymidylate synthase, thereby augmenting its pharmacological action. This combination allows lower doses of 5-FU to be effective while attenuating some of the associated side effects. It is important to note that leucovorin is not used as a rescue medication in the same manner as it is in methotrexate regimens.

Another useful drug in the pyrimidine class is cytarabine. Originally isolated from a Caribbean sea sponge, cytarabine is now synthesised chemically. It demonstrates potent anti-cancer activity and has proven an effective medication for leukaemias and lymphomas. Cytarabine is a prodrug whose active metabolite is ara-cytosine triphosphate. This metabolite is incorporated into DNA during replication, leading to the blockage of DNA polymerase processivity. As a result chain synthesis is disrupted. Cytarabine also induces miscoding in RNA. Common adverse effects of cytarabine include myelosuppression, which involves the suppression of bone marrow function leading to reduced blood cell production. Nausea and vomiting, cerebellar toxicity (manifesting as neurologic symptoms), and conjunctivitis are also common adverse effects of cytarabine.

Michael Bradaric (Rush Medical College)

This is an animated white-board presentation of information about antimetabolite drugs that are used to treat cancers. It includes a review of how the drugs disrupt de novo synthesis of purines and pyrimidines at the molecular level and where they act in the cell cycle, to induce cell cycle arrest and cell death.

The video was produced by Speed Pharmacology, and although it was made 3 years ago, the basic principles that it describes remain valid.

It is suitable for intermediate level learners.

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Chromatin function inhibitors

There are two classes of drugs that inhibit chromatin activity which are derived from plants, and are used in cancer chemotherapy regimens. 

The first class are semisynthetic derivatives of epipodophyllotoxin which is extracted from the American mayapple plant (Podophyllum peltatum) and consists of etoposide and teniposide. These drugs are glycosides and are potent inhibitors of chromatin activity due to targetting topoisomerase II (DNA gyrase) and DNA-binding complex I. These interactions destabilize the tension of the DNA molecule and contribute to double strand breaks. Tumor cells have difficulty repairing such breaks since they rely on the topoisomerase enzyme more than normal cells. Etoposide has clinical usefulness in solid tumors (testicular, lung, neuroblastoma etc.) as well as hematologic malignancies (leukemias and lymphomas). Myelosuppression (which is the major dose-limiting toxicity) is a well-known side effect. Hypotension and infusion-site pain/reactions are also commonly reported. Anaphylactic reactions are possible but less encountered. Paradoxically, when used for solid tumor treatment, these drugs can produce secondary leukemias (even though they can also treat such leukemias).  

The second class is derived from camptothecin, from the bark of a tree (Camptotheca acuminata) and consists of irinotecan. This is a prodrug which is converted by liver and GI enzymes (carboxylesterases) to the active metabolite, SN-38 which is 1000x more potent than the parent compound. Irinotecan is a potent inhibitor of topoisomerase I which leads to single-strand breaks which, in a similar fashion to double strand breaks observed with the first class, cancer cells have difficulty repairing. Irinotecan is used for several GI cancers, such as colon and pancreatic cancers. Diarrhea is the key dose-limiting toxicity, but myelosuppression and secondary leukemias are also possible. As benign as diarrhea sounds it is clinically significant, and must be monitored and managed, since it can have an impact on quality of life and can be life-threatening if dehydration ensues or if it is associated with neutropenia.    

 

Michael Bradaric (Rush Medical College)

This is a 14 minute lecture by Armando Hasudungan, on the different classes of chemotherapy agents. It begins with a review of the 4 phases of the cell cycle, to better understand where the chemo-drugs act to inhibit (cancer)cell proliferation and survival. At around 10 minutes in, topisomerase inhibitors are reviewed. Suitable for intermediate level learners, with background knowledge of cell biology.

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Immuno-oncology

Immune Checkpoint inhibitors

Immune checkpoint (IC) proteins are regulators of inhibitory signalling pathways that are essential for homeostasis of the T cell-mediated immune response. Immune checkpoint inhibitors are (generally) monoclonal antibodies that are used as a type of cancer immunotherapy and that act to re-establish immune detection and T cell-directed attack on tumours. Whilst these agents can be highly effective, they do not work for every patient, with certain cancers being inherently resistant to this pharmacological approach. Therapy-induced resistance to these agents can develop.  Barrueto et al. (2020) provide an extensive review of the immune checkpoints, and the molecular mechanisms that can lead to resistance (PMID: 32114384).

The image below is a simplified diagram of the ICs that are targeted by currently approved monoclonal antibodies. It focuses on the communications between tumour cells and T cells, but does not include T cell receptors and other accessory proteins that may be components of the functional checkpoint complexes.

Adapted from “Cell Immunotherapy (Layout)”, by BioRender.com (2022). Retrieved from https://app.biorender.com/biorender-templates

The PD-1/PD-L1 checkpoint

PD-1 (programmed cell death 1, a.k.a. PDCD1 or CD279) is a transmembrane protein on immune cells that interacts with the membrane-bound ligand PD-L1 (PD-1 ligand 1, or CD274). The PD-1/PD-L1 interaction is a key inhibitory checkpoint in T cell activation. Some cancers aberrantly express PD-L1 which allows them to evade immune surveillance and disrupts T cell-mediated anti-tumour immunity.

Therapeutic monoclonal antibodies have been developed to target either PD-1 or PD-L1 to correct the immunosuppressive effect of PD-1/PD-L1 pathway signalling within the tumour microenvironment, and to re-initiate T cell killing of tumour cells.

Approved antibodies (May 2022)

Antibody name/TN

Target

Year 1st approved

Indication(s)

nivolumab/Opdivo

PD-1

2014

mMel, NSCLC, RCC, HL, HNC, UC, CRC, HCC, SCLC, ESCC, mPM

pembrolizumab/Keytruda

PD-1

2014

mMel, NSCLC, HNC, HL, UC, GC, CC, HCC, MCC, RCC, SCLC, ESCC, EC, SCC

atezolizumab/Tecentriq

PD-L1

2016

BlC, NSCLC, BC, SCLC, HCC, mMel

avelumab/Bavencio

PD-L1

2017

MCC, UC, RCC

durvalumab/Imfinzi

PD-L1

2017

NSCLC, SCLC

cemiplimab/Libtayo

PD-1

2018

SCC, BCC, NSCLC

tislelizumab

PD-1

2019 (China only)

NSCLC (squamous & non- squamous), cHL, UC, HCC

dostarlimab/Jemperli

PD-1

2021

EC (mismatch repair deficient)

Abbreviations: BCC (basal cell carcinoma); BlC (bladder cancer); CC (cervical cancer); CRC (colorectal cancer); cHL (classical Hodgkin lymphoma); EC (endometrial cancer); ESCC (esophageal squamous cell carcinoma); GC (gastric cancer); HCC (hepatocellular carcinoma); HNC (head and neck cancer); MCC (Merkel cell carcinoma); mMel (metastatic melanoma); mPM (malignant pleural mesothelioma); NSCLC (non-small cell lung cancer); RCC (renal cell carcinoma); SCC (squamous cell carcinoma); SCLC (small cell lung cancer); UC (urothelial carcinoma)

The CTLA-4 checkpoint

CTLA-4 (cytotoxic T-lymphocyte-associated antigen 4, CD152) is expressed by T cells, and is crucial for maintaining T cell homeostasis, by providing an inhibitory signal that balances against molecular signals that stimulate T cells. It binds to CD80/86 on antigen-presenting cells and prevents co-stimulation of both the T cells and antigen-presenting cells.

To date only one CTLA-4-targeted therapeutic antibody has been approved for immuno-oncology use. Ipilimumab (Yervoy) was first approved for clinical use in 2011. Yervoy is indicated for the treatment of metastatic melanoma, RCC, CRC, HCC, NSCLC and, malignant pleural mesothelioma.

The LAG-3 checkpoint

LAG-3 (lymphocyte activating 3, or CD223) is another inhibitory checkpoint protein that regulates T cell function, and restrains immune attack on normal cells. Relatlimab is a monoclonal antibody that binds to LAG-3 and prevents it from interacting with its ligands, MHC class II and fibrinogen-like protein1 (FGL1). Relatlimab is approved for clinical use in combination with the PD-1 inhibitor nivolumab (Opdualag), as a therapy for malignant melanoma.

Adverse effects

All of these checkpoint inhibitors are administered by injection/infusion and induce systemic T cell activation. They commonly cause widespread side-effects such as dermatologic, gastrointestinal, endocrine, or hepatic autoimmune reactions that require monitoring and management. High dose corticosteroids may be required to suppress the hyperactivated immune system.

 

N.B.

It is instructive to note that the CTLA-4 immune checkpoint is also targeted as a therapeutic approach in autoinflammatory diseases, but in this field CTLA-4 mimetic peptides are used to promote the inhibitory activity of the CTLA-4/CD80/86 interaction on immune cell functions to down-modulate T cell-mediated inflammation and immune system hyperactivity. Two CTLA-4 mimetic fusion proteins are approved for clinical use

Drug INN/TN

Year 1st approved

Indication(s)

abatacept/Orencia

2005

severe rheumatoid arthritis, juvenile rheumatoid arthritis and active psoriatic arthritis

belatacept/Nulojix

2011

prophylaxis of organ rejection after kidney transplant

 

This informative Nature video produced by Dr Alison Halliday, describes how the immune system interacts with a tumour and how immunotherapy treatments are designed to work. At just 5 minutes, it is suitable for newcomers to the topic.

No votes yet

Immune Checkpoint inhibitors

Immune checkpoint (IC) proteins are regulators of inhibitory signalling pathways that are essential for homeostasis of the T cell-mediated immune response. Immune checkpoint inhibitors are (generally) monoclonal antibodies that are used as a type of cancer immunotherapy and that act to re-establish immune detection and T cell-directed attack on tumours. Whilst these agents can be highly effective, they do not work for every patient, with certain cancers being inherently resistant to this pharmacological approach. Therapy-induced resistance to these agents can develop.  Barrueto et al. (2020) provide an extensive review of the immune checkpoints, and the molecular mechanisms that can lead to resistance (PMID: 32114384).

The image below is a simplified diagram of the ICs that are targeted by currently approved monoclonal antibodies. It focuses on the communications between tumour cells and T cells, but does not include T cell receptors and other accessory proteins that may be components of the functional checkpoint complexes.

Adapted from “Cell Immunotherapy (Layout)”, by BioRender.com (2022). Retrieved from https://app.biorender.com/biorender-templates

The PD-1/PD-L1 checkpoint

PD-1 (programmed cell death 1, a.k.a. PDCD1 or CD279) is a transmembrane protein on immune cells that interacts with the membrane-bound ligand PD-L1 (PD-1 ligand 1, or CD274). The PD-1/PD-L1 interaction is a key inhibitory checkpoint in T cell activation. Some cancers aberrantly express PD-L1 which allows them to evade immune surveillance and disrupts T cell-mediated anti-tumour immunity.

Therapeutic monoclonal antibodies have been developed to target either PD-1 or PD-L1 to correct the immunosuppressive effect of PD-1/PD-L1 pathway signalling within the tumour microenvironment, and to re-initiate T cell killing of tumour cells.

Approved antibodies (May 2022)

Antibody name/TN

Target

Year 1st approved

Indication(s)

nivolumab/Opdivo

PD-1

2014

mMel, NSCLC, RCC, HL, HNC, UC, CRC, HCC, SCLC, ESCC, mPM

pembrolizumab/Keytruda

PD-1

2014

mMel, NSCLC, HNC, HL, UC, GC, CC, HCC, MCC, RCC, SCLC, ESCC, EC, SCC

atezolizumab/Tecentriq

PD-L1

2016

BlC, NSCLC, BC, SCLC, HCC, mMel

avelumab/Bavencio

PD-L1

2017

MCC, UC, RCC

durvalumab/Imfinzi

PD-L1

2017

NSCLC, SCLC

cemiplimab/Libtayo

PD-1

2018

SCC, BCC, NSCLC

tislelizumab

PD-1

2019 (China only)

NSCLC (squamous & non- squamous), cHL, UC, HCC

dostarlimab/Jemperli

PD-1

2021

EC (mismatch repair deficient)

Abbreviations: BCC (basal cell carcinoma); BlC (bladder cancer); CC (cervical cancer); CRC (colorectal cancer); cHL (classical Hodgkin lymphoma); EC (endometrial cancer); ESCC (esophageal squamous cell carcinoma); GC (gastric cancer); HCC (hepatocellular carcinoma); HNC (head and neck cancer); MCC (Merkel cell carcinoma); mMel (metastatic melanoma); mPM (malignant pleural mesothelioma); NSCLC (non-small cell lung cancer); RCC (renal cell carcinoma); SCC (squamous cell carcinoma); SCLC (small cell lung cancer); UC (urothelial carcinoma)

The CTLA-4 checkpoint

CTLA-4 (cytotoxic T-lymphocyte-associated antigen 4, CD152) is expressed by T cells, and is crucial for maintaining T cell homeostasis, by providing an inhibitory signal that balances against molecular signals that stimulate T cells. It binds to CD80/86 on antigen-presenting cells and prevents co-stimulation of both the T cells and antigen-presenting cells.

To date only one CTLA-4-targeted therapeutic antibody has been approved for immuno-oncology use. Ipilimumab (Yervoy) was first approved for clinical use in 2011. Yervoy is indicated for the treatment of metastatic melanoma, RCC, CRC, HCC, NSCLC and, malignant pleural mesothelioma.

The LAG-3 checkpoint

LAG-3 (lymphocyte activating 3, or CD223) is another inhibitory checkpoint protein that regulates T cell function, and restrains immune attack on normal cells. Relatlimab is a monoclonal antibody that binds to LAG-3 and prevents it from interacting with its ligands, MHC class II and fibrinogen-like protein1 (FGL1). Relatlimab is approved for clinical use in combination with the PD-1 inhibitor nivolumab (Opdualag), as a therapy for malignant melanoma.

Adverse effects

All of these checkpoint inhibitors are administered by injection/infusion and induce systemic T cell activation. They commonly cause widespread side-effects such as dermatologic, gastrointestinal, endocrine, or hepatic autoimmune reactions that require monitoring and management. High dose corticosteroids may be required to suppress the hyperactivated immune system.

 

N.B.

It is instructive to note that the CTLA-4 immune checkpoint is also targeted as a therapeutic approach in autoinflammatory diseases, but in this field CTLA-4 mimetic peptides are used to promote the inhibitory activity of the CTLA-4/CD80/86 interaction on immune cell functions to down-modulate T cell-mediated inflammation and immune system hyperactivity. Two CTLA-4 mimetic fusion proteins are approved for clinical use

Drug INN/TN

Year 1st approved

Indication(s)

abatacept/Orencia

2005

severe rheumatoid arthritis, juvenile rheumatoid arthritis and active psoriatic arthritis

belatacept/Nulojix

2011

prophylaxis of organ rejection after kidney transplant

 

This web resource provides information about immunotherapeutics, including access to their protein sequences and approval or development status. It includes antibodies, nanobodies and Ig-based fusion proteins (-fusps). Thera-SAbDab is updated regularly and is a good resource for those who seek in-depth information about these biologic entities.

No votes yet

Immune Checkpoint inhibitors

Immune checkpoint (IC) proteins are regulators of inhibitory signalling pathways that are essential for homeostasis of the T cell-mediated immune response. Immune checkpoint inhibitors are (generally) monoclonal antibodies that are used as a type of cancer immunotherapy and that act to re-establish immune detection and T cell-directed attack on tumours. Whilst these agents can be highly effective, they do not work for every patient, with certain cancers being inherently resistant to this pharmacological approach. Therapy-induced resistance to these agents can develop.  Barrueto et al. (2020) provide an extensive review of the immune checkpoints, and the molecular mechanisms that can lead to resistance (PMID: 32114384).

The image below is a simplified diagram of the ICs that are targeted by currently approved monoclonal antibodies. It focuses on the communications between tumour cells and T cells, but does not include T cell receptors and other accessory proteins that may be components of the functional checkpoint complexes.

Adapted from “Cell Immunotherapy (Layout)”, by BioRender.com (2022). Retrieved from https://app.biorender.com/biorender-templates

The PD-1/PD-L1 checkpoint

PD-1 (programmed cell death 1, a.k.a. PDCD1 or CD279) is a transmembrane protein on immune cells that interacts with the membrane-bound ligand PD-L1 (PD-1 ligand 1, or CD274). The PD-1/PD-L1 interaction is a key inhibitory checkpoint in T cell activation. Some cancers aberrantly express PD-L1 which allows them to evade immune surveillance and disrupts T cell-mediated anti-tumour immunity.

Therapeutic monoclonal antibodies have been developed to target either PD-1 or PD-L1 to correct the immunosuppressive effect of PD-1/PD-L1 pathway signalling within the tumour microenvironment, and to re-initiate T cell killing of tumour cells.

Approved antibodies (May 2022)

Antibody name/TN

Target

Year 1st approved

Indication(s)

nivolumab/Opdivo

PD-1

2014

mMel, NSCLC, RCC, HL, HNC, UC, CRC, HCC, SCLC, ESCC, mPM

pembrolizumab/Keytruda

PD-1

2014

mMel, NSCLC, HNC, HL, UC, GC, CC, HCC, MCC, RCC, SCLC, ESCC, EC, SCC

atezolizumab/Tecentriq

PD-L1

2016

BlC, NSCLC, BC, SCLC, HCC, mMel

avelumab/Bavencio

PD-L1

2017

MCC, UC, RCC

durvalumab/Imfinzi

PD-L1

2017

NSCLC, SCLC

cemiplimab/Libtayo

PD-1

2018

SCC, BCC, NSCLC

tislelizumab

PD-1

2019 (China only)

NSCLC (squamous & non- squamous), cHL, UC, HCC

dostarlimab/Jemperli

PD-1

2021

EC (mismatch repair deficient)

Abbreviations: BCC (basal cell carcinoma); BlC (bladder cancer); CC (cervical cancer); CRC (colorectal cancer); cHL (classical Hodgkin lymphoma); EC (endometrial cancer); ESCC (esophageal squamous cell carcinoma); GC (gastric cancer); HCC (hepatocellular carcinoma); HNC (head and neck cancer); MCC (Merkel cell carcinoma); mMel (metastatic melanoma); mPM (malignant pleural mesothelioma); NSCLC (non-small cell lung cancer); RCC (renal cell carcinoma); SCC (squamous cell carcinoma); SCLC (small cell lung cancer); UC (urothelial carcinoma)

The CTLA-4 checkpoint

CTLA-4 (cytotoxic T-lymphocyte-associated antigen 4, CD152) is expressed by T cells, and is crucial for maintaining T cell homeostasis, by providing an inhibitory signal that balances against molecular signals that stimulate T cells. It binds to CD80/86 on antigen-presenting cells and prevents co-stimulation of both the T cells and antigen-presenting cells.

To date only one CTLA-4-targeted therapeutic antibody has been approved for immuno-oncology use. Ipilimumab (Yervoy) was first approved for clinical use in 2011. Yervoy is indicated for the treatment of metastatic melanoma, RCC, CRC, HCC, NSCLC and, malignant pleural mesothelioma.

The LAG-3 checkpoint

LAG-3 (lymphocyte activating 3, or CD223) is another inhibitory checkpoint protein that regulates T cell function, and restrains immune attack on normal cells. Relatlimab is a monoclonal antibody that binds to LAG-3 and prevents it from interacting with its ligands, MHC class II and fibrinogen-like protein1 (FGL1). Relatlimab is approved for clinical use in combination with the PD-1 inhibitor nivolumab (Opdualag), as a therapy for malignant melanoma.

Adverse effects

All of these checkpoint inhibitors are administered by injection/infusion and induce systemic T cell activation. They commonly cause widespread side-effects such as dermatologic, gastrointestinal, endocrine, or hepatic autoimmune reactions that require monitoring and management. High dose corticosteroids may be required to suppress the hyperactivated immune system.

 

N.B.

It is instructive to note that the CTLA-4 immune checkpoint is also targeted as a therapeutic approach in autoinflammatory diseases, but in this field CTLA-4 mimetic peptides are used to promote the inhibitory activity of the CTLA-4/CD80/86 interaction on immune cell functions to down-modulate T cell-mediated inflammation and immune system hyperactivity. Two CTLA-4 mimetic fusion proteins are approved for clinical use

Drug INN/TN

Year 1st approved

Indication(s)

abatacept/Orencia

2005

severe rheumatoid arthritis, juvenile rheumatoid arthritis and active psoriatic arthritis

belatacept/Nulojix

2011

prophylaxis of organ rejection after kidney transplant

 

This NIH National Cancer Institute webpage provides more information about how immune checkpoint inhibitors (ICIs) work against cancer, and which types of cancer are currently treated with ICIs. There are links to further resources that cover additional aspects of cancer immunotherapy.

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Mitotic spindle poisons

Mechanism of action

Mitotic spindle poisons or anti-microtubule agents are important drugs for cancer therapy. Two drug classes will be discussed here: vinca alkaloids and taxanes. Microtubules are protein polymers that assist in cell movement and maintain cell shape/integrity. They regularly assemble and disassemble as required throughout the cell cycle. They are essential for cell division, to correctly separate the duplicated set of chromosomes and ensure each daughter cell gets the appropriate number of chromosomes during division. When the dissasembly/assembly of microtubules is disrupted, as happens with these drugs, cancer cell death can ensue. Anti-microtubule drugs are M phase specific, meaning they have their physiologic effect when the cancer cell enters the M phase of the cell cycle and mitosis occurs. Vinca alkaloids (vincristine) and taxanes (paclitaxel) both target the microtubule, but they have opposite mechanisms of action concerning where and when they bind. Vinca alkaloids bind to the tubulin subunits of the microtubule and prevent assembly of the microtubule complex. In contrast, taxanes bind to the microtubule itself, and prevent disassembly into constituent subcomponents.  

Administration, side-effects and mitigation strategies

Vinca alkaloids are potent vesicants, and when the patient is receiving the infusion apply warm packs (heat pads) and administer hyaluronidase to reduce the possible inflammation. Vinblastine is associated with a dose-limiting toxicity of thrombocytopenia. Additional toxicities include neurologic toxicities, constipation, and abdominal cramps. Vincristine has similar side effects. It is the most potent of the vinca analogs and can interfere with axonal transport (which rely on microtubules). These drugs are used for leukemias, lymphomas, and solid tumors. They are common in many regimens, despite their side effects and dangers. These drugs are fatal if administered intrathecally (in the spinal cord).  

Taxanes prevent the disassembly of microtubules. Paclitaxel is used in solid tumors and is associated with dose-limiting toxicity. Since they can be combined with other drugs, taxanes are usually prescribed before platinum analogs which seems to minimize the myelosuppression that can occur. Peripheral neuropathy, motor deficits, and myopathic effects are common. Hypersensitivity reactions can occur as well, usually during the first dose (almost half of the patients experience a reaction with the first dose). Reactions show a diffuse and intense erythroderma, tachycardia, pruritus, and chest tightness. To alleviate/combat this inevitable response, patients are premedicated with dexamethasone and diphenhydramine. The infusion may be stopped momentarily, and resumed after 30 mins. Infusions are stopped when respiratory compromise is evident, at which point the patient must switch to a new regimen without the taxane. Along the lines of preventing toxicity, the drug can be combined with nanoparticles to allow for increased concentration into the tumor without some of the capillary adverse effects. Common side effects to paclitaxel include a dose-limiting leukopenia, hypersensitivity reactions (already discussed), alopecia, cardiac toxicity, peripheral neuropathies, and mucositis. Docetaxel side effects include a more potent leukopenia, peripheral edema, peripheral neuropathies, and hypersensitivity reaction.

 

Michael Bradaric (Rush Medical College)

This 10 minute animated video from Osmosis from Elsevier covers microtubule structure, function and physiological role, in addition to outlining how the vinca alkaloids and taxanes exert their effects on cancer cells.

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Mechanism of action

Mitotic spindle poisons or anti-microtubule agents are important drugs for cancer therapy. Two drug classes will be discussed here: vinca alkaloids and taxanes. Microtubules are protein polymers that assist in cell movement and maintain cell shape/integrity. They regularly assemble and disassemble as required throughout the cell cycle. They are essential for cell division, to correctly separate the duplicated set of chromosomes and ensure each daughter cell gets the appropriate number of chromosomes during division. When the dissasembly/assembly of microtubules is disrupted, as happens with these drugs, cancer cell death can ensue. Anti-microtubule drugs are M phase specific, meaning they have their physiologic effect when the cancer cell enters the M phase of the cell cycle and mitosis occurs. Vinca alkaloids (vincristine) and taxanes (paclitaxel) both target the microtubule, but they have opposite mechanisms of action concerning where and when they bind. Vinca alkaloids bind to the tubulin subunits of the microtubule and prevent assembly of the microtubule complex. In contrast, taxanes bind to the microtubule itself, and prevent disassembly into constituent subcomponents.  

Administration, side-effects and mitigation strategies

Vinca alkaloids are potent vesicants, and when the patient is receiving the infusion apply warm packs (heat pads) and administer hyaluronidase to reduce the possible inflammation. Vinblastine is associated with a dose-limiting toxicity of thrombocytopenia. Additional toxicities include neurologic toxicities, constipation, and abdominal cramps. Vincristine has similar side effects. It is the most potent of the vinca analogs and can interfere with axonal transport (which rely on microtubules). These drugs are used for leukemias, lymphomas, and solid tumors. They are common in many regimens, despite their side effects and dangers. These drugs are fatal if administered intrathecally (in the spinal cord).  

Taxanes prevent the disassembly of microtubules. Paclitaxel is used in solid tumors and is associated with dose-limiting toxicity. Since they can be combined with other drugs, taxanes are usually prescribed before platinum analogs which seems to minimize the myelosuppression that can occur. Peripheral neuropathy, motor deficits, and myopathic effects are common. Hypersensitivity reactions can occur as well, usually during the first dose (almost half of the patients experience a reaction with the first dose). Reactions show a diffuse and intense erythroderma, tachycardia, pruritus, and chest tightness. To alleviate/combat this inevitable response, patients are premedicated with dexamethasone and diphenhydramine. The infusion may be stopped momentarily, and resumed after 30 mins. Infusions are stopped when respiratory compromise is evident, at which point the patient must switch to a new regimen without the taxane. Along the lines of preventing toxicity, the drug can be combined with nanoparticles to allow for increased concentration into the tumor without some of the capillary adverse effects. Common side effects to paclitaxel include a dose-limiting leukopenia, hypersensitivity reactions (already discussed), alopecia, cardiac toxicity, peripheral neuropathies, and mucositis. Docetaxel side effects include a more potent leukopenia, peripheral edema, peripheral neuropathies, and hypersensitivity reaction.

 

Michael Bradaric (Rush Medical College)

This short animated video quickly covers the history of microtubule discovery, and their path to becoming a therapeutic target for anti-cancer drug development. Suitable for beginner level learners. 

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PARP inhibitors

Poly(ADP-ribose) polymerase (PARP) inhibitors

This is a relatively new class of highly specialised anti-cancer drugs. They cause DNA damage that in normal cells, would be repaired by alternative DNA damage repair processes, such as BRCA-mediated homologous recombination 1. However, in certain cancers that carry genetic defects in these alternate pathways, the additive damage becomes lethal. This mechanism of promoting cell death by adding pharmacologically-induced DNA damage on top of the inbuilt BRCA deficiency in DNA repair is a manipulation of the concept of ‘synthetic lethality' 2. The original use of PARP inhibitors was based on their efficacy in cancers with germline loss-of-function mutations in either BRCA1 or BRCA2.

The first PARP inhibitor, olaparib, was approved by the US FDA and EU EMA in 2014. It was originally indicated to treat advanced ovarian cancer in patients with BRCA gene mutations.

Since 2014 a number of additional PARP inhibitors have been granted clinical use authorisations:

Rucaparib (2016 FDA). In 2020, rucaparib’s approval was expanded to include treatment of certain cases of BRCA mutation +ve metastatic castration-resistant prostate cancer.

Niraparib (2017 FDA and EMA)

Talazoparib (2018 FDA) was the first PARP inhibitor to be approved to treat locally advanced or metastatic HER2 negative breast cancers with deleterious germline BRCA mutations.

Pamiparib  (2021 China)

The currently used drugs are non-selective with respect to PARP isozymes. Inhibition of PARP1 appears to mediate the majority of the DNA-damaging effect of the drugs. Whereas, disrupting PARP2 activity is thought to be associated with their haematological toxicity (they are generally myelosuppressive). In the future, PARP1-selective inhibitors my offer an improved therapeutic index.

Initially, PARP inhibitors were used to treat selected advanced and recurrent cancers with BRCA mutations, particularly when other therapeutic options had been exhausted 3. More recently they have been authorised for both relapsed and newly diagnosed disease, with BRCA mutations or mutations in other DNA repair proteins (such as ATM serine/threonine kinase) 4.

References:

1 Helleday (2011) The underlying mechanism for the PARP and BRCA synthetic lethality: clearing up the misunderstandings PMID: 21821475 

2 Setton et al. (2021) Synthetic Lethality in Cancer Therapeutics: The Next Generation PMID: 33795234

3 Virtanen et al. (2019) PARP Inhibitors in Prostate Cancer–the Preclinical Rationale and Current Clinical Development PMID: 31357527

4 Groelly et al. (2023) Targeting DNA damage response pathways in cancer PMID: 36471053

This page is maintained by Drugs.com, and provides an up to date list of the PARP inhibitor drugs that are approved by the US FDA. It provides useful links to more details about the individual drugs.

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Poly(ADP-ribose) polymerase (PARP) inhibitors

This is a relatively new class of highly specialised anti-cancer drugs. They cause DNA damage that in normal cells, would be repaired by alternative DNA damage repair processes, such as BRCA-mediated homologous recombination 1. However, in certain cancers that carry genetic defects in these alternate pathways, the additive damage becomes lethal. This mechanism of promoting cell death by adding pharmacologically-induced DNA damage on top of the inbuilt BRCA deficiency in DNA repair is a manipulation of the concept of ‘synthetic lethality' 2. The original use of PARP inhibitors was based on their efficacy in cancers with germline loss-of-function mutations in either BRCA1 or BRCA2.

The first PARP inhibitor, olaparib, was approved by the US FDA and EU EMA in 2014. It was originally indicated to treat advanced ovarian cancer in patients with BRCA gene mutations.

Since 2014 a number of additional PARP inhibitors have been granted clinical use authorisations:

Rucaparib (2016 FDA). In 2020, rucaparib’s approval was expanded to include treatment of certain cases of BRCA mutation +ve metastatic castration-resistant prostate cancer.

Niraparib (2017 FDA and EMA)

Talazoparib (2018 FDA) was the first PARP inhibitor to be approved to treat locally advanced or metastatic HER2 negative breast cancers with deleterious germline BRCA mutations.

Pamiparib  (2021 China)

The currently used drugs are non-selective with respect to PARP isozymes. Inhibition of PARP1 appears to mediate the majority of the DNA-damaging effect of the drugs. Whereas, disrupting PARP2 activity is thought to be associated with their haematological toxicity (they are generally myelosuppressive). In the future, PARP1-selective inhibitors my offer an improved therapeutic index.

Initially, PARP inhibitors were used to treat selected advanced and recurrent cancers with BRCA mutations, particularly when other therapeutic options had been exhausted 3. More recently they have been authorised for both relapsed and newly diagnosed disease, with BRCA mutations or mutations in other DNA repair proteins (such as ATM serine/threonine kinase) 4.

References:

1 Helleday (2011) The underlying mechanism for the PARP and BRCA synthetic lethality: clearing up the misunderstandings PMID: 21821475 

2 Setton et al. (2021) Synthetic Lethality in Cancer Therapeutics: The Next Generation PMID: 33795234

3 Virtanen et al. (2019) PARP Inhibitors in Prostate Cancer–the Preclinical Rationale and Current Clinical Development PMID: 31357527

4 Groelly et al. (2023) Targeting DNA damage response pathways in cancer PMID: 36471053

This Outlook article written by Simon Makin was published in Nature in 2021. It is an excellent introduction to PARP inhibitors, their use and limitations in cancer therapy.

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