cancer therapy Flashcards
Name the 7 types of cancer therapy
- hormone therapy
- surgery
- bone marrow transplantation
- chemotherapy
- targeted therapy
- radiation therapy
- immunotherapy
Name the five pillars of cancer care
- surgery
- radiotherapy
- cytotoxic chemotherapy
- molecularly targeted therapy
- immunotherapy
How can surgery be used in cancer treatment?
- prevent cancer: removal of precancerous conditions (atypical moles, polyps to prevent colon cancer, removal of breast and ovaries
- diagnose and stage cancer: biopsy
- remove cancer (most effective at early stages)
- relieve symptoms (control spread, pain and haemorhages; surgical reconstruction)
- lower chance of recurrence (remove nearby normal tissue)
- repair damaged tissue (reconstructive or cosmetic)
- support other treatments (provide direct access to blood vessels, place special pump to deliver drugs)
- support body function (support breathing, getting enough nutritions)
Name two types of biopsies and explain them
incisional biopsy: part of the tumor is cut out
excisional biopsy: entire tissue is cut out
Explain different types of radiation therapy
- external beam radiation therapy: ionizing radiation (mostly photons) delivered by a linear accelerator, temporary
- internal radiation therapy:
a) seeds that contain radiation source are placed near the tumor –> temporary or permanent
b) systemic radiation therapy: radioactive drugs circulate through the body
How does radiation damage cancer cells?
damaging DNA of cells leading to cellular death
–> can either be indirect (production of ROS) or direct
–> single strand or double strand breaks (more difficult to repair)
What leads to radiation therapy resistance?
hypoxia as less ROS are formed
Are dividing or differentiated cells more sensitive for radiation damage?
dividing cells
How is the total dose of radiation given?
fractioned
What is the 4R principle of radiaton therapy?
- Repair
- Reassortment/ redistribution
- repopulation
- reoxygenation
What are the goals of chemotherapy?
- currative chemotherapy: elimination of all cancer cells
- palliative chemotherapy: relieve, slow down of progression
- neoadjuvant chemotherapy: shrink tumor size to allow less invasive surgery
- adjuvant chemotherapy: aims at cancer cells that are left in body after surgery to prevent recurrences
How do alkylating agents work as chemotherapy?
bind covalently via alkyl groups to DNA –> DNA damage -> DNA repair –> cell arrest –> apoptosis
Name different types of alkylating agents and example drugs
- Nitrogen mustard: Melphalan
- Nitrosoureas: Carmustine, Lomustine
- platinum-based antineoplastics: cisplatin, oxaliplatin
How do platinum-based antineoplastics work?
do not alkylate but cause covalent DNA adducts
Which chemotherapy drug works at which stage in the cell cycle?
- G1 to G2: Topoisomerase inhibitors, cytotoxic antibiotics
- S: antimetabolites
- M: antimicrotubule agents (beginning vinca alkaloids, later icrotubule inhibitors)
- whole cycle: alkylating agents
How do metabolites work as chemotherapy drugs?
interferes with normal cellular metabolism of nucleic acid –> structural similarity between natural metabolite and antimetabolite
Name example anti metabolites
- 5-Fluorouracil
- Methotrextate
- Folic Acid
How do topoisomerase inhibitors work?
- prevent DNA re-ligation and therefore causes DNA damage resulting in apoptosis –> cancer cells rely more on topo enzymes than healthy cells due to rapid replication
- inhibitors form a ternary complex with DNA and topo enzyme by forming hydrogen bonds
Name examples of topoisomerase inhibtors
- Camptohecin
- Etoposide
How do anti- microtubule agents work?
disrupt the M-phase of the cell –> cell cycle arrest –> apoptosis
Give examples of different anti- microtubule agents
- vinca alkaloids
- taxanes
Describe the tumor lysis syndrome in chemotherapy (kr!)
- occurs after massive destruction of tumor cells at the same time
- release of cellular content to the blood stream
- high blood electrolyte levels lead the renal insufficiencym cardiac arrhythmias, seizures and death due to multi organ failure
–> hyperuricemia, hyperkalemia, hyperphosphatamia and hypocalcemia
How can Tumor lysis syndrome be treated?
Rasburicase Enzyme (Elitek)
What is Leukemia?
cancer of the blood cells –> bone marrow makes large numbers of abnormal cells
What is myeloma?
cancer of plasma cells (white blood cells)
What is the role of leukemia stem cells in leukemia?
Leukemia is due to the presence of leukemia stem cells
When is hematopoietic stem cell transplantation performed?
patients who have certain cancers of the blood or the bone marrow
How does stem cell transplantation work?
recipients immune system is usually destroyed with radiation or chemotherapy before the transplantation
autologous: transplantation in which stem cells are removed from a person –> stored –> later given back to same person
allogeneic: healthy donor donates to patient recipient
What is the graft versus tumor effect in stem cell therapy? Compare autologous vs allogenic transplantation
newly generated immune cells attack residual cancer cells –> does not take place in autolgoues transplantation
What is the graft versus host disease in stem cell transplantation?
- inflammatory mechanism mediated by donor lymphocytes in the recipient
- tissues produce proinflammatory cytokines and chemokines
- increase in expression of key receptors on antigen presenting cells
- enhancing cross- presentation of polypeptide proteins to the donor immune cells
What is critical in determing the probability of graft verus host disease?
degree of human leukocyte antigen (HLA) matching –> HLA clases are matched as closely as possible
What are HLA molecules
present antigens to the T-lymphocytes and initiate specific immune responses encoded by MHC
How does hormone therapy work as a cancer treatment?
manipulation of the endocrine system
- drugs inhibit production / activity of steroid hormones
- administration of specific steroid hormones
when is hormonal therapy used as a cancer treatment?
used to treat cancers which are derived from hormonally responsive tissues: breast, prostate, endometrium, adrenal cortex
What is the role of estrogen in breast cancer?
- increases cell division and tumor progression
Name and explain hormonal therapy drugs
hormone receptor antagonists
- selective estrogen receptor modulators/ Receptor antagnists: tamoxiflen, Fulvestrant
- inhibitors of hormone synthesis (aromatse inhibitors): Exemestane
How do aromatse inhibtors work?
form permanent and deactivating bond with the aromatase or inhibit the synthesis of estrogen via reversible competition
Name two different types of clinical trails in personalized medicine
- umbrella clinical trails: multiple drugs tested against multiple genetic mutations within a single cancer type
- basket clinical trials: handful of drugs tested against a handful of genetic mutations across multiple cancer types
Give/ explain different examples for umbrella trials and basket trials
Umbrella: Cancer A (lung cancer) has many different Biomarkers (EGFR, BRAF) which all need different drugs to treat
basket: many different cancer types (lung cancer, melanoma) have the same biomarker (BRAF mutation) that can be treated with the same drug
How is a drug choosen in personalized medizine?
lab tests to assist in treatment decision-making –> circulating tumor cells are taken and grown in lab (mouse avatar or 3D cell culture) –> different drugs are tested on cancer cells
How does the immune system work against tumors?
- release of cancer cell antigens
- cancer antigen presentation
- priming and activation of APC and Tcells
- Trafficking of Tcells to tumors
- infiltration of Tcells into tumor
- recognition of cancer cells by Tcells
- killing of cancer cells
What is cancer immunotherapy?
artificial stimulation of the immune system to treat cancer to improve the immune system’s natural ability to fight cancer
What are immune checkpoint inhibitors?
negative regulatory molecules often found on the surface of T cells
–> regulate responses from self-proteins and protetct against autoimmune activity
Which inhibitory immune checkpoint pathways have drugs approved?
- CTLA4
- PD-1 and PD-L1
Name drugs against immune checkpoint inhibitors
PD-1: Nivolumab
CTLA-4: Ipilimumab
PD-L1: avelumab
What is the tumor mutational burden (TMB)
TMB is the number of somatic, non-synonymous, coding base mutations that occur in a defineed regio of the tumor genome
This high number of mutations is able to generate several neoantigens that can potenitally elicit immune responses against tumor
Which mutation is associated with resistance against immunotherapeutic drugs
mutations in STK11 (LKB1)
How does CAR-T cell therapy work?
- Tcells are isolated –> genetically engineered to express chimeric antigen receptor directed toward antigens on the patient’s tumor and then infused into the patient
What is the requirement of the chosen antigens in CAR-T cell therapy?
antigens must be highly expressed on the majority of cancer cells but largely absent on normal tissue
Why is the long term survival of CAR-Tcell therapy much lower?
antigen escape
Name CAR-Tcell drugs
- Tisagenlecleucel (leukemia)
- Axicabtagene ciloleucel (leukemia)
- sipuleucel-T (prostate cancer)
What are common side effects of CAR-Tcell therapy?
- cytokine release syndrome
- neurological toxicity
What is the core principal behind mRNA as a vaccination against cancer?
deliver the transcript of interest (immunogen) into the host cell cytoplasm where expression generates translated protein
What is targeted therapy?
Inhibition of proliferative signalling
Name examples of targeted therapy: EGFR inhibitors, cyclin dependent kinase inhibitors, telomerase inhibitors, anti inflammatory, PARP, proapoptotic BH3 mimetics, tyrosine kinase inhibitors
- EGFR inhibitors: Gefitinib
- cyclin dependent kinase inhibitors: Palbociclib
- telomerase inhibitors: Imetelstat
- anti- inflamatory drugs: celecoxib
- inhibitors of HGF/cMet: cabozantinib
- PARP inhibitors: Olaparib
- proapototic BH3 mimetics: venetoclax
- tyrosine kinase inhibitors: Imatinib
Where does imatinib bind?
binding in the TK domain of
- abl
- ckit
- PDGF-R
How does Imetelstat work?
is a oligonucleotide complimentary to the template region of the telomerase RNA component –> direct, competitive inhibition of telomerase enzymatic activity
How does celecoxib work?
inhibits Cox2
How does Olaparib work?
PARP1 inhibitor: causes multiple DDB
