Cancer Therapeutics Flashcards
What are some hallmarks of cancer?
Primary induction chemotherapy
What is the primary treatment strategy?
For what type of patients is it used?
With patients with advanced tumor/cancer, what is the primary goal of this chemotherapy?
- Drug treatment is primary treatment strategy- no surgery or radiation.
- For some patients may be curative.
Examples:
Adults; Hodgkins lymphoma, Non-Hodgkins lymphoma, germ cell cancers.
Children; acute lymphoblastic lymphoma, Wilms tumor, embryonal rhabdosarcoma.
- Also used for patients who present with advanced tumors/ metastatic disease for which no effective other treatment exists- alternative to supportive care alone.
- Goals are to palliate tumor-related symptoms, improve quality of life, prolong time to tumor progression, improve length of survival.
Neoadjuvant chemotherapy
For what patients is it recommended?
Is it used before or after surgery? Why?
What is the goal?
What king cancers does it help with?
- Use of chemotherapy in patients who present with localized cancer for which useful local therapies (surgery/ radiation) exist but may not be completely effective.
- Used before surgery or radiation, can allow sparing of vital normal organs.
- May also kill micrometastatic disease that is present.
- Goals are to increase the effectiveness of the surgery/ radiation- i.e. to maximize the destruction/removal of tumor tissue while minimizing damage to normal tissue and organs. Subsequent removal of residual tumor mass can allow determination of characteristics of residual tumor cells (allows studying the tumor cells).
- Used to treat: anal, bladder, breast, esophageal, head & neck, gastric rectal cancers, osteogenic (bone) and soft tissue sarcomas amongst others
**treating a tumor with drugs before taking them to surgery**
Adjuvant chemotherapy
Used before or after surgery?
What is the goal?
Why is it difficult to response to the drug?
- Use of chemotherapy in patients after local treatment modalities such as surgery/ radiation treatment
- Goal is to reduce the incidence of localized AND systemic recurrence by killing metastatic tumor cells
- Can increase the effectiveness of the surgery/ radiation and improve overall survival and increase relapse free survival.
- Used to treat: breast, colorectal, gastric, non small cell lung cancers, melanoma.
•Because primary tumor has been removed, difficult to measure response to the drug- relapse free survival and overall survival are major end points.
What are some of the general principles governing the use of cancer chemothetapy?
Does it have a small or large therapeutic window?
What can cause differences in people treated with the same agents?
Do all patients experience the same efficacy and toxicity of durgs?
Why is pharmacogenetics important?
•Conventional cancer chemotherapy has one of the smallest therapeutic windows in medicine. (Not as true for the new “targeted” therapeutics.)
**Therapeutic window is a range of doses that produces therapeutic response without causing any significant adverse effect in patients. Generally therapeutic window is a ratio between minimum effective concentrations (MEC) to the minimum toxic concentration (MTC).
- Variability in pharmacokinetics between patients caused by differences in renal/hepatic function, age, prior surgery etc. can cause significant differences between people treated with the same agent.
- Patients may experience marked differences in efficacy and toxicity- e.g. a heavily pre-treated patient may experience more bone marrow toxicity at the same doses/ schedules compared with a minimally pre-treated patient.
- Pharmacogenetics is important. Small differences in drug handling can have major effects- e.g. Polymorphisms in the promoter region of the Uridine diphosphate glucuronyltransferase (UGT1A1) gene associated with toxicity caused by irinotecan treatment. Phase II enzyme responsible for inactivating the active metabolite of irinotecan.
Generl principles of cancer chemotherapy: combining drugs/resistance
Can a single drug cure cancer?
What increases with increase in the use of drug combinations/different ones?
Why combination therapy works?
- With rare exceptions single drugs at clinically tolerable doses are unable to cure cancer. 3 or more different drugs may be required and more is probably better- e.g. childhood leukemia cure rate increases when active drugs increased from three to seven. However, toxicity is usually increased too.
- Mutations can lead to drug resistance and tumors may already contain resistant cells when they are detected-leading to Darwinian natural selection for the tumor cells harboring the mutations.
- Probability that a given tumor contains resistant cells is a function of the tumor size and the inherent mutation rate. Larger tumors likely worse, but small tumors can be bad too. A 1cm tumor may have > 1 Billion tumor cells
- If they are capable of continued self-renewal and growth, a few resistant cells can eventually expand to repopulate the tumor mass even if the initial clinical response appears very good- therefore even patients who appear to achieve complete remission can suffer relapse. These tumor cells are usually harder to kill.
Why combination therapy works:
Heterogeneous tumor cells sensitive to different drugs, and allow th drugs to have an effect.
General principles for combining drugs:
- Drugs that are at least partially effective against the same tumor when used alone should be combined. Not necessarily true for newer “targeted” agents where better knowledge of mechanisms of action means that we may be able to combine a drug that doesn’t work at all with one that will make it effective or tumor-specific.
- Try to select drugs that have toxicities that do not overlap- e.g. try not to give people two drugs that both damage their liver. This can lead to a broader range of side effects but minimizes the risk of lethal interactions.
- Try to use drugs at their optimal doses & schedules.
- Keep treatment free intervals as short as possible while allowing recovery of most sensitive normal tissue target (often bone marrow).
- Avoid removal or dose reduction of a drug from the combination because this may allow outgrowth of a resistant tumor subclone.
Why do cytotoxic drugs that affect DNA, cytoskeleton are also successful at times?
Anticancer drugs usually kill cancer cells via what mechanism?
What is the side effect of this type of killing?
Apoptosis
Side effect: unable to activate an immune response, which is a problem when cancer cells, which most often need an adaptive cell response.
Apoptosis
Mitochondrial permeabilization controlled by 3 flavors of BCL family proteins
1- Pro-survival are the_______
2- Pro-apoptotic effectors
3- BH3 only regulators
1- Bcl2, Bcl-xL, MCL1
2- Bax and Bak
3-BH3 regulate the levels of the previous two (regulates protein-protein interactons)
How do BH-3 proteins works?
BH3-only proteins cause mitochondrial permeabilization by directly activating pro-apoptotic effectors like BAK or by de-repressing anti-apoptotic family members like MCL-1.
How does chemotherapy works then, if one of the cancer hallmarks is to evade apoptosis:
Cancer cells are usually more (not less) sensitive to apoptosis than their normal counterparts. Which means that they undergo apoptosis more easily when using drugs to fight them.
This increases sensitivity of cancer cells allows the use of chemotherapeutics with small therapeutic window to treat cancer effectively in some situations.
Why does chemotherapy works from an methaphoric perspective:
Priming for apoptosis and commitment to cell death. Apoptosis behaves as a switch-like threshold event. As such, it can be considered like a cliff. Cells that have a predominance of pro-apoptotic proteins are relatively close to the cliff’s edge, and are considered primed for apoptosis. Even modest amounts of apoptotic signaling will push them over the cliff’s edge and force them to commit to cell death. Cells that have a predominance of antiapoptotic proteins are relatively unprimed. Apoptotic signaling may push them toward the cliff edge, but it will be hard to make them go over the edge
What is BH3 profiling?
Which mitochondria are considered primed for apoptosis, which ones are not?
BH3 profiling:
In BH3 profiling, mitochondria are exposed to systematically titrated doses of synthetic BH3 peptides, and the resulting mitochondrial outer membrane permeabilization (MOMP) is measured.
Purple spheres represent intermembrane space proteins, like cytochrome c, that are released when MOMP occurs.
Mitochondria that exhibited a relatively great amount of MOMP at relatively low concentrations of BH3 peptides are considered relatively primed for apoptosis.
Those that exhibit little or no MOMP at high doses of BH3 peptides are considered relatively unprimed.
How can BH3 profiling can predict clinical response to chemotherapy?
Pretreatment BH3 profiling predicts clinical response to chemotherapy in AML.
BH3 profiling was performed on myleoblasts from patients before induction therapy.
Also explains why cancer cells are more sensitive than normal
Low mitochondrial priming in normal mouse and human cells correlates with resistance to chemotherapy
What are some of the problems of the traditional cytotoxic drugs?
Do they usually target the defect that cuased the tumor?
- Kilsl normal cells along with the tumor cells- since therapeutic window is small.
- This often affects dividing cells- e.g. bone marrow, intestinal tract- these normal cells are already “primed” to be easy to kill.
- Usually not targeting the defect that caused the tumor.
Things to know so far….
Cancer Chemotherapy- the present/future
Traditional “cytotoxic” agents that target core cellular functions (DNA, cytoskeleton, metabolic pathways etc.) that are important in all cells but (hopefully) preferentially kill cancer cells for the reasons we talked about last time.
•“Targeted” agents that go after Hallmarks of Cancer and thus (hopefully) selectively kill cancer cells with little or no effect on normal cells.
These things tend not to be used in isolation, many patients get treated with both either separately or in combination.
Common mechanism of chemoresistance
Alkylating agents react with DNA
How does this happen?
What is an example drug?
what effect does it have in DNA?
In breast cancer, it is combined with what?
What is it used for?
It is inactive, so it must be metabonized by the______.
Cell with high levels of what enzyme are resistant to cyclophosphamide? What tissues have high levels and show low toxicity?
They form covalent chemical adducts and interstrand crosslinks in DNA.
–>If not repaired, prevents DNA replication- recognized as DNA damage activating apoptosis.
Cyclophosphamide:
- Nitrogen mustard- produces inter-strand crosslinks in DNA
- Most frequently used alkylating agent
- Breast cancer: combine with doxorubicin (Adriamycin), methotrexate, 5-fluoruricil.
- Also used for lymphomas, childhood tumors, various solid tumors.
- Inactive, must be metabolized to active (by liver) form- eventually phosphoramide mustard.
- Metabolite (4-hydroxy cyclophosphamide) is substrate for aldehyde dehydrogenase (ALDH) which forms carboxyphosphamide- Not an active alkylating or cytotoxic agent. Up to 70% of the drug may be excreted as this inactive metabolite.
- Cells with high levels of ALDH are resistant to the drug. Hematopoietic and intestinal stem cells have high levels- explains relatively low toxicity compared with other alkylating agents.
Cisplatin and analogues
How do they work?
Cisplatin show high ________, in contrast carboplating is less toxic to kidney.
In what type of cancers are they usually effective?
- Used as anti-cancer drug since 1960’s
- Derivatives: carboplatin, oxaliplatin, others in development.
- Derivatives less toxic: e.g. cisplatin shows high nephrotoxicity (ameliorated to some extent by aggressive pre-hydration) but carboplatin less toxic to kidney- primarily caused by changes in PK.
- They work by Crosslink DNA (usually intrastrand CpG crosslinks) making replication impossible and triggering apoptotic response.
- Effective in testicular cancer, also commonly used in ovarian, head & neck, lung, bladder cancer.
Platinum compounds Toxicity
5-Fluorouracil- Toxicity
Topoisomerase interacting agents
Topoisomerases mechanisms of action
How do they work?
What is an example?
Topoisomerase resistance
Increased drug efflux- particularly important for etoposide, _________.
doxorubicin
Antimicrotubule agents- Vinca alkaloids
When are they used?
To which microtubule do they bind?
•Vinblastine, vincristine
- Naturally occurring compounds
- Used in pediatric malignancies, hematopoietic tumors and some solid tumors.
- Bind to tubulin at microtubule ends.
At higher concentrations cause depolymerization- break down microtubules.
Vinca Alkaloids- resistance
Vinca Alkaloids- Toxicity
Which one is particularly toxic to Neurons (nerve cells)?
Which one lead to myelosupression and neutropenia?
Taxanes
1- What part of the microtubule do they bind?
2- In contrast to vinca alkaloids, they __________ microtubule depolimerization, altering dissociation rates at both ends of the microtubule.
1- interior surface of microtubules
2- stabilize against
Taxanes - Resistance
Toxicity
Hormonal agents
What type of cancer does it treat?
Tamoxifen is used for what kind of tumors?
What is the function of letrozole?
Function of leuprolide?
Inhibitors of steroid receptors: Resistance
Hormonal agents: Toxicity
What is seen in women?
What is seen in men?
Antibodies
- Rituximab- Anti CD20 used to treat B cell tumors
- Trastuzumab/ Herceptin- Anti-Her2 breast cancer.
- Bevacizumab/Avastin- Anti-VEGF colon cancer
- Ipilumumab and other immune checkpoint inhibitors- melanoma
- Can work by inhibiting function of target- e.g. Avastin blocks VEGF from stimulating its receptor to promote angiogenesis. In addition, cell mediated toxicity (e.g. by Natural Killer cells) can result from antibody binding to tumor antigens.
- A few Immunoconjugates deliver toxins, chemotherapeutic drugs, radioisotopes etc. to tumor cells.
Therapeutic antibodies are an example of a treatment that relies on the ______1______ for efficacy
1- Levels of the target for efficacy
Immune checkpoint inhibitors circumvent tumor strategies to avoid immune system
**CTLA-4 reduce T cell activation to maintain self-tolerance- block to enhance T cell activation.
**PDL-1 mechanism to inhibit T cell effector function;
Tumors that have unregulated PDL-1 can evade immune-mediated destruction
Toxicities
Kinase Inhibitors
What is the main kinase inhibitor representative of targeted therapy?
With the exception of Imatinib, are kinase inhibitors very effective in curing people?
- “targeted’ to defects that cause tumor development.
- May be associated with low (but never no) toxicity.
- May be highly effective- poster child for targeted therapy is Imatinib treatment of CML & GIST.
- CAUTION: with the possible exception of Imatinib in CML, we have few if any examples where kinase inhibitors cure people. Acquired resistance to the therapy almost always happens.
Imatinib
How does it work?
How does resistance to imatinib happens?
Imatinib binds in the active site of the enzyme, and inhibits in function.
Imatinib
Frequent mutations in Imatinib-resistant CML is T315I- the bulky isoleucine side chain prevents drug binding but does not alter ATP binding or hydrolysis- i.e. the mutant kinase is still active.
Apoptosis Targeted Drugs: BH3 mimetics
BCL proteins as drug targets, what is an examples of a drug that inhibits Bcl-2? How does it work?
What do BH3 mimetic do?
Venetoclax: BCL2 inhibitor. The first drug designed to disrupt a specific protein-protein interaction
How it works:
Venetoclax blocks the anti-apoptotic B-cell lymphoma-2 (Bcl-2) protein, leading to programmed cell death of CLL cells.
-Overexpression of Bcl-2 in some lymphoid malignancies has sometimes shown to be linked with increased resistance to chemotherapy.
****BH3 mimetics push a tumor cell closer to its apoptotic threshold
Some of the learning objectives
