20th lecture (cancer therapy)

Question 1

What are the 2 categories for cancer therapy?

Answer 1

Local: surgery, radiotherapy
Systemic: Chemotherapy, hormone therapy, Targeted therapy (we target specific pathways and cells), immunotherapy.

Question 2

what approach do we use to treat cancer?

Answer 2

its a complex approach: surgery followed by radiotherapy.

different protocols for different cancer types.

Question 3

who decides the type of treatment?

Answer 3

a tumor board; oncologist, radiologist, surgeon, pathologist, geneticist, psychologist.
together they determine the optimal therapeutic strategy.
Curative therapy: cure the patient
palliative therapy: supportive therapy to alleviate the pain for the patient.

Question 4

what do surgeons do to treat tumors?

Answer 4

• they have a choice between curativa vs palliative surgical intervention. They also check the regional lymph nodes to see if the cancer is metastatic.

Question 5

what does radiotherapy do?

Answer 5

ionizing radiation causes double stranded breaks in the DNA. Sometime used after surgery and can be used in combination with chemotherapy.

Question 6

what does Chemotherapy do?

Answer 6

Its like “carpet-bombing” targeting everything and can cause damage to all cells.
The drugs can be cytostatic (stop the cell cycle), and cytotoxic (toxic to the cell directly)
Can damage the DNA.

Question 7

Neo-adjucant therapy definiton?

Answer 7

when a treatment is used BEFORE the main therapy to help the main therapy succeed.
Such as: radiation to shrink tumor and the surgery to remove it.

Question 8

what is INDUCTION in the context of chemotherapy?

Answer 8

the primary therapy is called induction chemo therapy.

Question 9

why are we scared of chemotherapy?

Answer 9

because it has severe side-effects: because it affects normal cells as-well. Secondary malignancies can arise even after many year of chemotherapy.

Question 10

what are some of the agents used for chemotherapy?

Answer 10

• alkylating agents and platinum based regimens: they bind to the DNA and form DNA-adducts. Thus the DNA cannot function from then on.
• Plant alkaloids: toxic compounds from plants, they block the cell division mechanism. (block the mitotic spindle).
• Antimetabolities: DNA or RNA analogues. If they are incorporated they terminate the DNA and RNA synthesis and the cell will go to apoptosis.

Patients receive certain cycles and combinations of chemotherapy drugs.
Letters are used to designate the component of each drug: i.e. CHOP or BEACOPP.

Question 11

what kindof people respond well to chemotherapy.

Answer 11

(pediatric tumor) younger patients as they are healthy enough do deal with the toxic affects of the treatment.
90%, of patients with acute myloid lymphoma are successfully treated with chemotherapy.

Question 12

future of oncology?

Answer 12

instead of the “one size fits all” we instead try to find one drug for one patient at the right dose. “The right drug to the right patient at a right dose at the right time”

Question 13

Describe the “success story of personalised medicine” in the context of cancer therapy.

Answer 13

The natural course of chronic myeloid leukemia (CML), is:
The patiet is present in chronic phase which lasts 3-5 years where we have abberant granulocyte production.
The disease then progresses to an accelerated phase, which then progresses to blast crisis: when it looks like acute leukemia. The patient dies within a month. 5 year survival rate.
In 1960 it was found that the Philadelphia chromosome had a casual relationship between the chromosome abnormality observed and chronic granulocyte leukemia. In 1973 it was found that this Philadelphia chromosome was actually a reciprocal translocation between chromosomes 9 and 22. 1985 they identified that the genes for BCR (breakpoint cluster region) on 22 and abl (tyrosine kinase) on 9 become neighbors. They will form a fusion gene that will code for a fusion protein that will send a continuous signals to the cell (continuous phosphorylation). The cell will divide rapidly leading to cancer. In 1995 a doctor found that he could use a thyrosin kinase inhibitor to treat the disease. Imatinib was found. The result was 80% have a 5-year survival rate. Now known as Glivec. Resistance was seen due to a mutation in the BCR-ABL1.

Question 14

how do we measure the therapy of the CML (chronic myeloid leukemia)

Answer 14

We use PCR to detect any mutations and we also montior BCL-ABL1 levels to see if the therapy is working.

Question 15

under what conditions would we see a BCL-ABL1 level rise?

Answer 15

-mutation leading to decreased response to a therapy.

A mutation analysis and a 2nd generation of the drug can be used.

Question 16

The process of drug trials/clinical trials?

Answer 16

Drug discovery (5000-10,000) drugs simulated on the computer, then about 250 are tested on cell cultures (preclinical trials). Human testing occurs in the clinical trials. Phase 3 clinical trails where the drugs are tested on thousands of patients and the results are compared to the BAT (best available treatment).
Phase 4 = real world results are seen.

Drugs are sometimes tested on a patient that has failed to respond to all other treatments. Targeted therapies and immunotherapy are being tested in the trails.

Question 17

what are the 2 types of the targeted therapy?

Answer 17

• monoclonal antibodies: (MAPS) they are specific against certain structures.
• Small molecule inhibitors:

Question 18

what is oncogene addiction?

Answer 18

a tumor cell, despite its plethora of genetic alterations, can seemingly exhibit dependence on a single oncogenic pathway or protein for its sustained proliferation and/or survival.

The more complex the genetic background of a certain mutation the less likely targeted therapy is going to work.

Question 19

what kindof treatment was used for chronic lymphocytic leukemia?

Answer 19

it was treated with chemo-immunotherapy (R-FC) which was complimented with rituximab (anti-CD20)
but patients with TP53 mutations the chemo-immunotherapy will only kill the cells which are wild type. The TP53 mutated cells are selected, resistance developed in a short time frame.
Targeted therapy ibrutinib which was a BTK inhibitor. This increased survival rate for patients.
ibrutinib caused BTK mutation that resulted in ibrutinib to no longer work, so a new drug called enetoclax was used BCL2 inhibitor.

Question 20

Describe the process/mechanisism of how immunotherapy works.

Answer 20

Anti-PD-1 can bind to the T-cell via PD-1 and anti-PD-L1 can bind to the tumor cell via PD-L1, inhibiting the function of the immune system.
we can use immuno checkpoint inhibitors to inhibit the PD-L1 and PD-1.

CTLA-4 has a similar function and if we bind an anti-CTLA-4 to it we can release the inhibition of the cell, this will activate the immune system.

The immuno checkpoint inhibitors appeared in the last 5 years.

Question 21

who are no candidates for targeted therapy?

Answer 21

patients who have a KRAS mutation

Question 22

describe the CAR T-cell therapy (gene therapy).

Answer 22

we patients and we perform leukopheresis (remove some T-cells). We perform genetic manipulation of the T-cells and create the CAR T-cells. The CAR T-cells will recognize the tumor and fight against the tumor efficiently.