Pharm Sci 310: Cancer Treatment
The goals of this lecture are to familiarize students with some basics of tumor formation, treatments for
cancer, and the side effects of cancer treatment.
Reading (you are only responsible for the parts of these that we specifically discuss in class). These are all
written for a lay audience.
http://www.cancer.org/treatment/treatmentsandsideeffects/treatmenttypes/chemotherapy/whatitish
owithelps/index.htm
http://www.cancer.org/Treatment/TreatmentsandSideEffects/TreatmentTypes/Chemotherapy/Che
motherapyPrinciplesAnIn-depthDiscussionoftheTechniquesanditsRoleinTreatment/index
Drugs to know
Paclitaxel (Taxol) and nab-paclitaxel (Abraxane)
Imatinib (Gleevec)
Nivolumab (Opdivo) (and diagnostic test PD-L1 IHC 28-8 pharmDx)
Some hints on drugs: chemicals that target kinases usually end in "nib"
Monoclonal antibodies usually end in "mab"
Lecture slides are attached.
Introduction
Cancer Treatments Overview
Cytotoxic (cell killing agents)
Targeted therapies
Targeting the tumor microenvironment
Progress/future of cancer therapy
SOME DEFINITIONS
Tumor- abnormal mass of cells resulting from defects in normal
control of cell survival, proliferation and differentiation
Benign tumor: does not invade the surrounding tissues or spread
to other parts of the body. But can they cause health issues?
Malignant tumor (=cancer): can invade surrounding tissue and
spread to other parts of the body (metastasize), will get worse
Often named after where they arise
What is technical definition of chemotherapy?
EARLIEST CANCER THERAPIES
Edwin Smith Papyrus- about 3000 BC describes
tumors/ulcers of breast removed by cauterization but “There
is no treatment”.
Celsus (Roman physician 28-50 B.C.) "After excision, even
when a scar has formed, none the less the disease has
returned.”
Galen (2nd century Greek doctor) did write that some breast
tumors could be cured by excision if caught early enough
mid-1800s anesthesia allowed more surgeries
Late 1800s Thomas Beatson tested oophorectomy for breast
cancer (hormone ablation)
A VERY BRIEF HISTORY OF CANCER THERAPY
1900- radiation
Around 1950- cytotoxic chemotherapies nitrogen mustard and
methotrexate
1990s- “targeted therapies” monoclonal antibodies to target
tumors
2000s- “targeted therapies” kinase inhibitors, anti-angiogenesis
agents
2010- prostate cancer cellular immunotherapy
2010s- “checkpoint inhibitors” as immune modulators
2017- genetically modified T cells (CAR-T)
1)
2)
3)
4)
5)
6)
7)
CANCER TREATMENTS
Surgery
Radiation
Chemotherapy
“Targeted” therapies
Immunotherapies
Hormonal therapies
Hyperthermia (heat)
REGIMENS
-
Name of drug(s)
Dose
How often
How long
How given
Introduction
Cancer Treatments Overview
Cytotoxic (cell killing agents)
Targeted therapies
Targeting the tumor microenvironment
Progress/future of cancer therapy
CANCER CHEMOTHERAPY
- Usually refers to cytotoxic (= cell killing agents)
- Generally target rapidly dividing cells
- Usually small molecules
MICROTUBULES
-Important part of cellular structure (cytoskeleton)
NIH
-Also act as “tracks” for transport of materials within cell
MICROTUBULES- CONTINUED
http://dms.dartmouth.edu/compton/photos/photos/html/Mitotic_spindle.html
- Part of the mitotic spindle
- Made of polymerized tubulin subunits
- Dynamic structures
Skop lab
MICROTUBULE (SPINDLE) POISONS
Example: Paclitaxel (Taxol)
Originally discovered as natural product isolated
from bark of yew tree
What is its mechanism of action?
PACLITAXEL (TAXOL)
Originally thought to induce a “mitotic arrest” by
“poisoning” mitotic spindle
At clinical doses, now thought to cause abnormal
chromosome segregation
http://stm.sciencemag.org/content/6/229/229ra43/F1.expansion.html
PACLITAXEL (TAXOL)
- Variety of solid tumors
- Some common acute side effects- nausea, vomiting,
hypotension, hypersensitivity
- Delayed toxicities: neuropathy, myelosuppression
- Nanoparticle formulation nab-paclitaxel (Abraxane)
may reduce some toxicities
,
PACLITAXEL (TAXOL)
- Resistance: increased expression of proteins that
pump drug out of cell; expression (increased or
mutant) of proteins that promote mitosis or block cell
death; changes in tubulin
,
Which of the following statements
is CORRECT?
• A) Nab-paclitaxel generally causes more
toxicities than paclitaxel
• B) Paclitaxel is thought to destabilize
microtubules and therefore block microtubule
polymerization
• C) One mechanism of paclitaxel resistance is
that cancer cells increase expression of
proteins that pump the drug out
• D) Paclitaxel would be an example of a
targeted cancer therapy
OTHER SIDE EFFECTS CYTOTOXIC AGENTS
CAN CAUSE
- GI Effects (Nausea, vomiting, diarrhea or
constipation)
- Alopecia
- Changes in the taste of food
- Neuropathies
- Bone marrow (myelosuppression)
- Impact fertility
- Secondary malignancies
- Some are vesicants
- Hand-foot syndrome
- ”Chemo brain”
Introduction
Cancer Treatments Overview
Cytotoxic (cell killing agents)
Targeted therapies
Targeting the tumor microenvironment
Progress/future of cancer therapy
TARGETED THERAPIES
- Goal- attack tumor cells while sparing normal
cells
- Target molecular pathways involved in cancer
cell survival/progression
TARGETED THERAPIES: KINASE INHIBITORS
Target enzymes that are different in cancer cells than other cells
Kinases are frequent “drugable targets”
What do kinases do?
Some kinases have abnormal activity in cancer (over-expression,
mutation, other mechanisms)
EXAMPLE: CML
Chronic myeloid leukemia (CML) frequently harbors a
specific chromosomal abnormality called a translocation
(the specific translocation found in most CML cells is
called the Philadelphia chromosome)
- Philadelphia chromosome can be present in ALL
RESULT OF TRANSLOCATION: BCR-ABL fusion
The result of the Philadelphia chromosome: fusion "oncoprotein" called
BCR-ABL that harbors constitutively active ABL kinase activity
Druker, B. J.
Blood
2008;112:48084817
RATIONAL THERAPY: IMATINIB (GLEEVEC)
Ciba-Geigy (now Novartis) were testing small molecule
kinase inhibitors (including trying to find ones that would
target ABL)
Brian Druker had cell culture models for CML
Tested the compounds to find one that seemed to be
selective for killing CML cells
Result: Imatinib (Gleevec)
RATIONAL THERAPY: IMATINIB (GLEEVEC)
Estimated CML 5 year survival now 95%
Imatinib also inhibits other kinases important in other
tumors
- In addition to CML and ALL used to treat other
cancers/conditions driven by cKIT, PDGFRA
IMATINIB (GLEEVEC): ISSUES
-Side Effects: Fluid retention, muscle cramps, others
-Resistance: Common cause is due to point mutations in
BCR-ABL
- Drugs have been developed to inhibit Imatinib-resistant
BCR-ABL
Introduction
Cancer Treatments Overview
Cytotoxic (cell killing agents)
Targeted therapies
Targeting the tumor microenvironment
Progress/future of cancer therapy
Nivolumab (OPDIVO)
“checkpoint”
DAKO.Agilent
Nivolumab= anti-PD1 antibody
Nivolumab (OPDIVO)
- Side effects include rash and fatigue
- Can also more rarely see severe immune-related
adverse events (irAEs)
- Thought to be caused by general immunologic
enhancement
Nivolumab (OPDIVO)
- Can be used in therapy for a variety of solid tumors
- Sometimes in combination with an inhibitor of
another “checkpoint”, a kinase inhibitor, or
traditional chemotherapy
- Not all patients respond- Why?
- One hypothesis is that higher mutational load =
better response
- For some tumor types, FDA requires screening
tumor for PD-L1 expression (biomarker for
response)
Nivolumab (OPDIVO)
PD-L1 IHC 28-8 pharmDx
DAKO.Agilent
Introduction
Cancer Treatments Overview
Cytotoxic (cell killing agents)
Targeted therapies
Targeting the tumor microenvironment
Progress/future of cancer therapy
• How have cancer rates and survival
rates changed over time?
LIFETIME RISKS IN US
Developing invasive cancer: 39.5%
2nd leading cause of death
2020: estimated 1.8 million new cases of cancer will be
diagnosed
Cancer statistics, 2022
CA A Cancer J Clinicians, Volume: 72, Issue: 1, Pages: 7-33, First published: 12 January 2022, DOI: (10.3322/caac.21708)
Cancer statistics, 2022
CA A Cancer J Clinicians, Volume: 72, Issue: 1, Pages: 7-33, First published: 12 January 2022, DOI: (10.3322/caac.21708)
Cancer statistics, 2022
CA A Cancer J Clinicians, Volume: 72, Issue: 1, Pages: 7-33, First published: 12 January 2022, DOI: (10.3322/caac.21708)
Cancer statistics, 2022
CA A Cancer J Clinicians, Volume: 72, Issue: 1, Pages: 7-33, First published: 12 January 2022, DOI: (10.3322/caac.21708)
The future?
More personalized medicine
Better vaccines/immunotherapy
Better uses/modifications of existing drugs
Circumventing resistance
New drug targets
Detection/prevention
Better drug delivery
Lifestyle changes
True or false
• Cancer mortality rates per 100,000
people have been increasing in the past
30 years
SUMMARY
Definitions (benign, malignant, metastatic, chemotherapy, etc.)
History of cancer treatment
Cancer treatments
Chemotherapy
Targeted therapy
Immunotherapy
War on Cancer: detection, prevention or treatment?
The future