Transcript Modalities in Cancer Therapy

Modalities in Cancer Therapy
Folder Title: Therapy
TtlTreat
Updated: April 18, 2012
Will complete Taylor Black 60-Minutes Story
Why We Do Cancer Therapy Research
Read:
“In the Elevator at the Princess Margaret Hospital”
See tpfondy.mysite.syr.edu
Also on course web-site.
Therapeutic Modality Options
Surgery
Radiation
Chemotherapy (Including Hormonal Therapy)
See Chapter 16: Rational Treatment of Cancer
Immunotherapy
See Chapter 15: Crowd Control – Tumor
Immunology and Immunotherapy
Host Response Modification
Gene Therapy (and Virotherapy?)
“Specific-Targeted” Therapies:
Monoclonal antibodies or pharmaceuticals directed to
errors in signaling pathways, to signal receptors, or to
other key oncoproteins or suppressor proteins.
Features of Surgical Intervention
• Highly Tumor-specific and Effective
• Technically Sophisticated and of Limited Applicability
• Access depends on economic status of country*
*See Cancer in the Developing World (later)
• Useless for Extensive Systemic Disease or for Unrecognized
Metastases
• Depends on Pathological Identification:
– (Must know where the cancer is)
• Traumatic, Immunosuppressive, & Dangerous
• Can Induce Systemic Spread
• Patient Refusal and Opting for Alternative Medicine
• Physical Modality – Emergence of Cellular Resistance is not possible
Therapies Involving Electromagnetic Radiation:
Part 1: X-Ray
• External physical intervention with a chemical target (DNA)
• Not Especially Tumor-specific; Damage to Normal Tissue Can Limit Utility
• Limited Utility Against Extensive, Systemic Disease
• Can be Valuable for Debulking Large Local Tumor or
Reducing Tumor Size to Permit Surgery
• Second Malignancies Can Be Induced
• Combination with Radio-sensitizers Can Improve Anti-tumor Specificity
• Limited by Tumor Heterogeneity and Selection for Radiation-resistant
Variants
Radiate
Therapies Involving Electromagnetic Radiation:
Part 2: Photodynamic Therapy, Hyperthermia, Neutron
Capture, Microwave or Radiowave Therapy
• External physical intervention with a physical target:
–
(the cancer cell or cancer mass)
• Must know where the cancer mass is
–
–
–
–
Must be able to direct the physical intervention
e.g. Laser-directed microwave
Utility against cancers not accessible to surgery
May use antibody to bind metal to tumor target for microwave destruction
• Damage to normal tissue must be circumvented
• Emergence of resistance is unlikely
Radiate
Possibilities with Ultra-sonic Radiation: Part 1
External physical intervention with a physical target: the size and sonic
sensitivity of the cell.
Emergence of cellular resistance based on cancer cell biochemistry is
not possible.
Target is a necessary physical state (enlarged cell size at mitosis) through
which the dividing cancer cell must pass, no matter how it got to that state.
May not have to know where the cancer cells are.
Possibility of Whole-Body Ultra-sound*
* Poster by Kenny Shin, Matthew Koslow, and Alison Eimer on whole body
sonication of Zebrafish.
Should be applicable to metastasizing cells including carcinomas and sarcomas
in the circulation or in the lymphatic drainage.
Treatment of circulating blood in extra-corporeal shunt or in appendages:
(See hand-cooling used by San Francisco 49 er’s).
See poster by Ryan Burns, Lindsay Rechan, Alexis Lodico, Ashley Nieves, and
Karina Acevedo on sonication of flowing leukemia cells in a glass-coil.
Possibilities with Ultra-sonic Radiation: Part 2
Possible to magnify the differences in sonic sensitivity between normal and
cancer cells by treatment with cytoskeletal-directed agents or other agents
that preferentially affect leukemia cell size.
Chemotherapeutic agents produce cell enlargement in cells that are damaged
that may still remain viable.
Possible to link ultra-sonic therapy with cell cycle-directed chemotherapy.
Resistance of red blood cells to low frequency ultra-sound is key to the concept.
Tumor-specific or tumor selective anti-neoplastic agents:
Chemotherapy
Cell-cycle Directed Anti-neoplastic Drugs
Cell Cycle Phase
Drug
Target
Go – G1
Taxol
Microtubules
(stabilize)
S-Phase
Ara-C (Cytosine
arabinoside)
DNA synthesis
S- G2
VP-16 (Etoposide)
Topoisomerase II
M
Vinca-alkaloids
Taxol
Microtubule disrupters
Microtubule stabilizer
Non-cell-cycle specific
Alkylating agents:
Cis-platinum
Cyclophosphamide
Nucleophiles (e.g.
DNA)
Cancer may sometimes initially respond to drug treatment
but then the cancer recurs and is no longer responsive the
agent that originally was effective. This is what is called
drug __ __ __ __ __ __ __ __ __ __ .
0 of 5
I read an essay about something I learned at the Princess
Margaret Hospital in Toronto.
Where was I when I learned this message about cancer?
__ __ __ __ __ __ __ __ .
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Immunotherapy of Cancer
• Potentially Highly Tumor-Specific
• Can be Effective Against Disseminated Disease Including
Unrecognized Micro-metastases
• Probably of Limited Value Against Extensive Advanced
Disease
• Can Involve Severe, Sudden Onset Life-threatening
Treatment-limiting Side-Reactions
• Limited by Tumor Heterogeneity, Selection for
Unresponsive Variants, and Emergence of
Immune-Escape
ImmunOpt
Host-Response Modification in Cancer
Management
Potentially Less Intrusive than Other More-Aggressive
Modalities
Treating Host Supporting Cells to Reduce their ability to
promote tumor growth (e.g. anti-angiogenesis)
Host stromal cell interactions supporting tumor growth:
“Respect Thy Neighbor!” Science, Feb. 6, 2004
(BIO 501 Web-Site: Password-protected Link)
Host Mod
Gene Therapy for Cancer
• Potentially Highly Tumor-Specific
• Accessibility of Cell Targets Is a Major Obstacle
for General Application
• May Have Great Value in Combined Modality
Approaches
• Potentially Dangerous Side-Reactions from Viral
Vector Delivery Agents
GeneTher
“Viro-Therapy”
Using Viruses to Treat Cancers
(See Scientific American, October 2003, pp 69 to 75
Virotherapy with Transductional Targeting:
Adenovirus engineered to bind to an infect only cancer cells
Does not infect normal cells
Adenovirus multiplies in cancer c ells.
Cancer cell burst and disperse virus to infect other cancer cells.
Virotherapy with Transcriptional Targeting:
Adenovirus engineered to replicate under control of tumor promoter genes.
Virus replicates only in cancer cells that have the tumor-specific promoter.
Cancer cell bursts and disperse virus particles to infect other cancer cells.
Lethal immune-responses in persons sensitized to adenovirus vector.
Will show photos of adenovirus virotherapy using Document Camera
Virotherapy with
Transductional
Targeting
Scientific
American,
October 2003
Virotherapy
with
Transcriptional
Targeting.
Scientific
American
Combined Modality Therapies for Cancer
Surgery and Radiation
Adjuvant Chemotherapy: Surgery and Chemotherapy
Radio-sensitizers: Chemotherapy and Radiation
Chemotherapy and Host-Response Modification
• Induction of Differentiation by Chemotherapeutic Agents
• Induction of Apoptosis by Chemotherapeutic Agents
Immunotherapy and Gene Therapy
Genetically Engineered T-Cells
Chemotherapy with Ultra-sonic Disruption?
Combined
Emergence of Drug Resistance
Figure 16.23 The Biology of Cancer (© Garland Science 2007)
Table 16.2 The Biology of Cancer (© Garland Science 2007)
The picture below is showing an important mechanism
involving cancer drug resistance. What is the structure
that is shown inserted into the cell membrane?
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Physician’s Desk Reference
Oncology Reference Guide
203 Oncology Treatment Agents
Published in 2003
Costs of Cancer Treatment vs Efficacy
Non-small-cell Lung Cancer Treatment with Erbitux (cetuximab)
18 Week course of treatment, $40,000
Average Life Span Increase vs Standard Therapy: 1.2 Months
Avastin (bevacizumab) $30,000 to $62,000 per patient per course of
treatment.
Efficacy marginal
Costs of non-curative treatments
Off-Label use of approved medications
See Science, March 25, 2011, p. 1545-7, David Malakoff
Science, Vol 331, March 25, 2011, p. 1547. Average Costs for a single patient.
1st year after diagnosis vs continuing care vs terminal year care
Ratio of
Mortality to
Incidence.
If the ratio is
large the
prospects for
survival are
bleak.
25 Mar
p. 1548
Questions for Society and the Health-Care System
And You
Do We Treat Everyone?
Regardless of Condition, Age, or Life Expectancy?
Whether the treatments are clearly beneficial or not?
Do we pay for off-label drug treatments (using an
agent approved for one cancer to treat another cancer
for which efficacy has not been tested)
This question is set to anonymous. I will not know what choice you
selected and this is not graded.
Biology of Cancer is not a usual course for a Biology Department.
We have had this course going for 35 years.
Should we keep it or drop it?
1. Drop it. It belongs in a medical school.
2. Keep it, but it needs a lot of improvement to be as valuable
as it could be in an undergraduate biology program.
3. Keep it. It is a valuable option among our undergraduate
courses.
4. No opinion on this.
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Application of Ultra-sound to Attached Cells:
In Situ or Metastatic
1. Cell must detach and round up in order to divide.
2. Attached cells can be made to detach by treatment with
cytoskeletal-directed agents.
3. Ultra-sound may be applicable to disseminated attached
metastatic cells, not just to leukemia-lymphoma.
Modulation of Ultra-sonic Treatment
1. Can vary the sonic frequency (wavelength).
2. Can vary the intensity.
3. Can vary the timing to correspond with cell cycle and
cell treatment responses.
4. Opportunity for multiple ultra-sonic treatments
repeated at minutes, hours, or days.
5. Host toxicity is likely to be manageable.