Cancer Theraputics

Question 1

How to Alkylating agents work?

Answer 1

React with DNA in all phases of the cell cycle
Provided electron rich atoms that form covalent bonds with DNA molecules that results in cross linking and intrastrand linking. This does not allow topoisomerase and helicase to uncouple the stands of DNA prior to transcription

Question 2

Types of alkylating agents and some examples of each?

Answer 2

Nitrogen Mustards
- Melphalan
- clorambucil
- cyclophosphamide/ifosfamide

Alkyl Sulfonates
- Busulfan

Nitrosoureas
- Carmustine

Triazenes
- temozolamide

Platinums
- Cisplatin
- Carboplatin
- Oxaliplatin

Question 3

Alkylating agents toxicities?

Answer 3

BM suppression
Impact on intestinal mucosa
Alopecia
Pulmonary fibrosis
Hepatotoxicity
Gondal Toxicity, teratogenesis

Question 4

Which Alkylating agents are Vesicants? What is a vesicant?

Answer 4

Alkylating agents with a short half life are vesicants
- nitrosoureas and nitrogen mustards

Vesicants are agents that can cause localized damage at the site of infusion

Question 5

Which alkylating agents produce Acrolein via the CYP450 pathway? what is the complication of Acrolein?

Answer 5

Cyclophosphamide/ifosfamide are nitrogen mustards that are metabolized to Acrolein via CYP450
Acrolein causes hemorphagic cystitis

Question 6

What are the toxicities of platinums?

Answer 6

Toxicities of platinums are similar to alkylating agents toxicities because platinums are a form of alkylating agent
- Immunosupression
- GI mucisal upset causing ulcers, dia, nausea and vomiting
- Cation wasting nephropathy (helped with lots of rehydration)
- Peripheral neuroapthy (sensory and motor, may be exacerbated by the cold)

Question 7

Explain the mechanism of action of antimetabolites?

Answer 7

Work by incorperating DNA base anologues or inhibiting production or restoration of DNA bases

Question 8

Examples of antimetabolites chemo agents?

Answer 8

5-FU (and the pro drug capecitabine)
Methotrexate
Pemetrexed
Cytarabine
Gemcitabine
6-Mecaptapurine
Cladribine

Question 9

Antimetabolite side effects?

Answer 9

BM suppression
GI toxicity (Ulcers, dia, nausea, vomiting)
Skin rash (hand and foot, can desquamate in severe cases)
Hepatotoxicity
Arthraliga and myalgias

Question 10

Explain the mechanism of action of topoisomerase inhibitors?

Answer 10

Toposiomerase untangles (or tangles) up DNA to allow for DNA replication
By inhibiting topoisomerase, the cell cannot undergo mitosis

irinotecan and topotecan, inhibitors of topoisomerase I, and etoposide and teniposide, inhibitors of topoisomerase II

Question 11

There are two types of topoisomerase inhibitors. What are some examples of each?

Answer 11

Topoisomerase 1 inhibitors:
- Irinotecan, topotecan

Topoisomerase 2 inhibitors:
- Doxorubicin, Epirubicin
- Etoposide, teniposide
- Dactinomycin, mitoxantrone

Question 12

Topoisomerase inhibitor toxicities?

Answer 12

Vesicants
GI upset (profound diarrhoea)
Secondary melignancy (leukaemia)
Anthracyclines (doxorubicin, epirubicin) - cardiotoxicity (usually HFrEF) and red urine (colour of the drug)

Question 13

Explain the MoA of Antimicrotubule agents?

Answer 13

Interferes with the microtubules such that alignment or organelles for mitosis is disrupted and cell death occurs

Question 14

Types of microtubule agents and some examples?

Answer 14

Taxanes:
- Paclitaxel, Docetaxel, Cabazitaxel

Vinca alkyloids
- Vincristine

Question 15

Toxicities of microtubule agents?

Answer 15

Neuropathy - can be irreversible, usually UL and LL sensory, can be tinitus
Docetaxel can cause capillary leak syndrome mimicking peripheral oedema

Question 16

Name some broad types of endocrine therapies?

Answer 16

ER and PR suppression with SERMs / aromatase inhibitors
- used in Breast, avarian, and endometrial cancers

Testosterone suppression with GnRH agents or novel hormone antagonists
- Used in Prostate cancer

TSH suppression with thyroxine
- used in thyroid cancer

Somatostain anologues
- Used in NETs

Question 17

How do targeted therapies work in general?

Answer 17

Cancers cells may be highly dependant on an over expressed onogenic pathways such as the EGFR, KRAS, BRAF, MEK pathway or the HER2+ pathway
This allows for the used of drugs that target this pathway
Higher therapeutic indicies can be achieved due to the relative lack of expression on other cells

Usually -nib (TKIs) and -mabs (monoclonal antibodies) are targeted therapies
-nibs are small molecule TKIs and may get intracellular
-mabs are large molecules and connot get intracellular

Question 18

What are the two cell targets of immunotherapies?

Answer 18

CTLA-4 inhibibition (older immune checkpoint inhibitors)
PD-1 / PDL-1 inhibition (modern immune checkpoint inhibitors)

Question 19

Explain the molecular MoA of CTLA-4 inhibitors

Answer 19

MHC peptide complex on APC recognized by TCR
Second signal for T cell activation from CD80/86 to CD28
CTLA-4 is also expressed on T cells, it has much higher affinity for CD80/86 compared to CD28. When present it preferentially binds to CD80/86 causing T cell inactivation
Blockade of CTLA-4 allows CD28 to bind CD80/86 therefore T cell is upregulated

Question 20

Explain the molecular MoA of PD-1 / PDL-1 inhibitors

Answer 20

PD1 on T cell usually binds PDL1/2 on APC resulting in downregulation of T cell activity
Tumour cells over express PDL1, this results in inhibition of tumor specific effector T cells
Blocking PD1 or PDL1 allows for recognition in the periphery (compared to just recognition in the LN as with CTLA4i)

Question 21

Does immunotherapy work best against highly mutates cancers, or non highly mutated cancers?

Answer 21

Highly mutated cancers have more neoangigen production allowing more opportunity for Immune system recognition

Question 22

Immunotherapy toxicities ?

Answer 22

Immune activation results in -itis’s
Almost any body system or organ can be effected
In the event of a severe immune reaction, immunosupression is key as this is an immune driven process. Therefore steroids are primary engagement management
In severe reaction, may need to consider ceasation and other immunosupressive drugs such as infliximab or mycophenylate

Do not cause neutropenias!

Question 23

What are the organs most commonly affected by immunotherapy toxicities?

Answer 23

Thyroid
- 12% of pts
- treat if symptomatic
- Prednisone PO or methylpred IV in acute setting
- Hypothyroid -> give levothyroxine
- Hyperthyroid -> can use carbimazole if severe, but prednisolone should be sufficient

Colitis
- 5-10% of pts
- Grade 1: <4 stools more than baseline - Rx loperamide
- Grade 2: 4-6 stools more than baseline - w/h immunotherapy, PO or IV steroids with taper when improved
- Grade 3: >7 stools more than baseline - w/h immunotherapy, IV steroids. If refractory over 3-4 days then add infliximab or vedolizumab
- Grade 4 - perforation - permanantly dicontinue immunotherapy. IV steroids. If refractory over 3-4 days then add infliximab or vedolizumab. surgical review

Renal dysfunction
- G1: Cr <1.5x baseline (or ULN) - continue immunotherapy
- G2/3: Cr 1.5-6x baseline (or ULN) - w/h immunotherapy, PO pred. If refractory treat as G4
- G4: Cr >6x baseline (or ULN) - permanantly dicontinue immunotherapy. IV steroids with PO taper

Pneumonitis
- Rare, <1%
- Treat if symptomatic, not just based on radio findings

Question 24

Explain the MoA of antibody drug conjugates?

Answer 24

Chemotherapy agent attached to antibody. Uses antibody to deliver chemo payload to the area

Question 25

What are theronostics? give some examples?

Answer 25

Theranostics is a combination of therapeutic and diagnostic
Usually a binding vector (for binding to a host cell surface receptor) bound to a radioactive source (usually beta emitter)
- this can deliver radiation to the local area (theraputic) and can also be used in nuc med diagnostics (diagnostic)

Some examples:
- PSMA labelled Lutetium for Pr Ca
- 177Lu-Dotate for NETs of GI tract

Question 26

Name some antiemetic agents for highly emetogenic regimes?

Answer 26

Netupitant (neurokinin 1 antagonist)
Palonosetron (serotonin receptor antagonist)
Dexamethasone (steroid)

Question 27

Name some supportive care agents for non immunotherapy related diarrhoea?

Answer 27

Loperamide (non alagesic opioid, acts directly on the bowel smooth muscle)
Lomotil - non analgesic opioid
Octreotide - short acting somatostatin anologue (second line therapy)
Consider cholestyramide or creon if previous gut anatomy changes