Chapter 17

Why are stomach cancer fatalities falling?

H. pylori screenings started

Does surgical intervention on benign tumors help to prevent later stages of cancer?

No, it increases mortality

What is the best screening for cancer today?

Histopathological analysis

The removal and analysis of biological tissue is?

Histopathology

The accidental discovery of an asymptomatic tumor is known as?

Incidentaloma

What are two very common incidentalomas?

Pancreatic neuroendocrine tumors and papillary thyroid carcinomas

What are indolent tumors?

Dormant tumors with very low invasive and metastatic potential

Primary tumors are most likely disseminated by the time someone is diagnosed with what kind of tumor?

A highly aggressive tumor

What tumors can be surgically removed or treated with cytotoxic therapies before dissemination occurs?

Tumors of an intermediate grade

Are there well developed treatments for metastatic tumors?

No

Breast cancer patients who are treated with cyclophosphamide later develop what cancer due to side effects of this medication?

Acute myelogenous leukemia

Isolating all the RNA from a cancer cell and subjecting it to sequencing to compare it with a normal cell (RNA-seq) creates what?

Gene expression profiles

Incidence of breast cancer is increasing, however, mortality is decreasing due to?

The ease of diagnosis and early intervention

What is an extremely diverse cancer that leads to extreme variation in prognosis patient to patient?

Diffuse large B-cell lymphoma (DLBCL)

What does DLBCL stand for?

Diffuse large B-cell lymphoma

What are the most common cells for cancer to lie?

Epithelial, endothelial, immune, and other stromal cell types

Why is it difficult to do RNAseq on cancer cells?

The surrounding tissue often contaminates the results

What is the solution to contamination with RNAseq?

Single Cell RNA Seq (scRNAseq)

What is scRNAseq

Single Cell RNA Seq

Gene expression arrays are important for what branch of biology?

Functional genomics

__________ ________ is a field of molecular biology that attempts to describe gene functions and interactions. __________ ________ make use of the vast data generated by genomic and transcriptomic projects.

Functional Genomics

What is the most common amount of genes reviewed in gene expression arrays?

10,000

__________ is the large-scale, systematic study of the the entire set of proteins produced by an organism, system, or cell.

Proteomics

Out of the 1,300 anti-cancer therapies that can be discovered within the year, how many usually make it through?

4 or 5

What are the four anti-cancer therapy classes?

Small molecule drugs, monoclonal antibodies, gene therapy using viral vectors, and vaccines

The theory that surgical oncologist live by is what?

Small tumors will inevitably develop into large tumors

Surgical oncology works fairly well in what cancer, yielding a 95% patient survival after five year?

Early-stage colorectal carcinomas

When it was discovered that skin exposed to X-rays burns, what field of anti-cancer therapy was invented?

Radiation oncology

A very essential tool in reducing post-surgical relapse is what?

Focused adjuvant radiotherapy

Radioactive isotopes administered by drugs or coupled to monoclonal antibodies are?

Radionuclides

Implantation of radioactive sources carried in small capsules into organs or tumors is known as?

Brachytherapy

Mustard gas reduced lymphomas through what action that kills blood cells?

Alkylating action

Patients treated with chemotherapy often relapse because?

Chemo drugs are highly cytotoxic and mutagenic

What drug prevented DNA and RNA synthesis using purine and pyrimidine anologs?

Aminopterin

One of the earliest chemotherapies developed from Taxus brevifolia that blocks the breakdown of microtubules at the end of mitosis ceasing cytokinesis is?

Taxol

What are two microtubule-depolymerizing agents?

Colcemide and Vincristine

What are two DNA modifiers used to generate crosslinks in DNA between two guanines that caused the cure rate of testicular cancer to go from 10% to 95%?

Cisplatin and Carboplatin

What are the four most common multi-drug protocols?

ABVD, CHOP, FOLFOX, and TIP

What is ABVD therapy used for?

Hodgkin’s lymphoma

What is CHOP therapy used for?

Non-Hodgkin’s lymphoma

What is FOLFOX therapy used for?

Colorectal cancer

What is TIP therapy used for?

Testicular cancer

What are the most common side effects from multi-drug therapies?

Diarrhea, peripheral neuropathy, kidney disease, liver disease, weakened cardiac muscles, and bone marrow suppresion

Additional cancer treatment—such as chemotherapy, radiation, hormone, or targeted therapy—given after primary treatment (usually surgery) to destroy remaining cancer cells and lower the risk of recurrence is known as?

Adjuvant treatments

The administration of therapeutic agents before a main treatment is known as?

Neoadjuvant treatment

For solid tumors, what is recommended before surgical excision?

Neoadjuvant treatment

How do cancer cells acquire multi-drug resistance?

Inactivate pro-apoptotic genes and tumor suppressor genes

The rate of drug absorption, distribution, metabolism, and excretion is known as?

Pharmacokinetics (PK)

What does PK stand for?

Pharmacokinetics

How a cell actually responds to a drug is known as?

Pharmacodynamics (PD)

What does PD stand for?

Pharmacodynamics

What causes a greater chance of ceasing of mitosis within a cancer cell?

Greater differentiation

Cancer cells must do what to prevent themselves from ceasing mitosis?

Dedifferentiation

Successful anti-cancer drugs do what two things?

Induce apoptosis and differentiation

Acute Promyelocytic Leukemia (APL) is caused by translocations on what chromosomes?

15 and 17

APL stands for?

Acute Promyelocytic Leukemia

APC causes the fusion of what two proteins?

PML and RAR

What receptor initiates signaling pathways that cause cells to differentiate after binding to retinoic acid?

Retinoic acid receptor (RAR)

What does RAR stand for?

Retinoic acid receptor

How does differentiation cause mitosis to cease?

It makes cancer cells behave more like normal tissue

How does PML-RAR stop cell differentiation?

It represses normal RAR

What is a treatment of APL that causes ubiquitination of PML-RAR and leads to complete remission with chemotherapy?

All-trans-retinoic acid (ATRA)

What does ATRA stand for?

All-trans-retinoic acid

What treatment is similar to ATRA and is used for regression of pre-malignant lesion that lead to head and neck cancers?

13-cis-retinoic acid (13cRA)

Shutting down what pathway triggers apoptosis?

Akt signaling

Selectivity and specificity with a focus on high TI is the goal of?

Proteins as targets for drug development

What treatments are easily synthesized, more likely to penetrate tumor cells, and are only inhibitory are known as?

Low molecular weight organic compounds

What are the downsides to low molecular weight organic compounds as cancer treatments?

They could possibly inhibit p53 on accident and cannot restore caretaker or gatekeeper function

If you shut down H-ras, K-ras, and bcr-abl to kill a tumor and then later reactivate them to find out the tumor came back, this is known as?

Oncogene addiction

Does oncogene addiction happen with all proteins such as with myc in mice?

No

If a cancer uses a protein to develop in its early stages, could it stop using that protein in its later stages, leading to a safe reactivation of that protein?

Yes

If a protein has enzymatic function and a well-defined catalytic cleft, it is known as?

Druggable

Where do small molecules love to bind on proteins?

In a catalytic cleft

If a protein lacks catalytic clefts, such as with myc and fos, it is known as?

Undruggable

Estrogen and progesterone receptors lack catalytic clefts, would they be considered druggable?

Yes because they can bind pseudo-ligands instead (tamoxifen

Only ___ in ____ proteins are druggable

1 in 5

Is catalyticc cleft always enough for druggability?

No

GTP bound ras is druggable or undruggable?

Undruggable

GDP bound ras is druggable or undruggable?

Druggable

Should tyrosine phosphatases be targed for chemotherapeutic drugs?

No because they can reverse the effects of proliferation

Why is it difficult to synthesize protein-protein druggable target?

Association of proteins involves multiple points of contacts (except Mdm2-p53)

Why is it difficult to target kinases for small molecule drugs?

Most kinases are similar with similar catalytic clefts which would create non-specific binding

What are the three points of concern with rational drug design?

Specificity, selectivity, and binding affinity

Bystander effects could reveal other clinical applications for drugs such as with?

Gleevec (Bcr-Abl fusion protein inhibition)

Drug compounds that are ________ cannot easily enter cells.

Hydrophobic

Drug compounds that are _________ can easily enter cells.

Hydrophilic

What does MTD stand for?

Maximum tolderated dose

Both the patient and doctor do not known if they are giving placebos making clinical trails what?

Double blinded studies

Drugs are tested for toxicity, side-effects, and maximum tolerated dose in both healthy and sick humans during?

Phase I

Drugs are tested on cancer patients based on indicators such as tumor type and stage during?

Phase II

Drugs are tested on patients who have relapsed and are refractory (non-responsive) to established therapies during?

Phase III

Drugs are tested for statistical significance during?

Phase III

Drugs are tested and pinned against other similar drugs during?

Phase IV

How does resistance develop in tumors?

Acquisition of drug pumps, drug metabolism, DNA repair, neutralization of apoptotic machinery, or the inability to pass drug through plasma membrane

What is the most common transmembrane drug efflux pump?

MDR1

Reciprocal translocation between chromosome what and what causes Bcr-Abl fusion (Philadelphia Chromosome)?

9 and 22

Which protein has tyrosine kinase activity that is found to be leukemogenic?

Abl

What drug binds to the catalytic cleft of Bcr-Abl?

Gleevec

Gleevec only targets _ of __ human tyrosine kinases?

4 of 90

Why is Gleevec better at treating CML than kinase inhibitors?

Kinase inhibitors block ATP but Gleevec changes Bcr-Abl conformation