Modalities in Cancer Therapy

Folder Title: Therapy(NoTP)

Updated: April 13, 2013

TtlTreat

Complete The Introduction to Taylor Black Story by TPF

Taylor Black 60-Minutes Story Later

Why We Do Cancer Therapy Research

Read: “In the Elevator at the Princess Margaret Hospital”

See tpfondy.mysite.syr.eduAlso on course web-site.

Therapeutic Modality OptionsSurgery

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 1External 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.

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.

Possibilities with Ultra-sonic Radiation: Part 2

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-alkaloidsTaxol

Microtubule disruptersMicrotubule stabilizer

Non-cell-cycle specific Alkylating agents:Cis-platinumCyclophosphamide

Nucleophiles (e.g. DNA)

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

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 cellsDoes not infect normal cellsAdenovirus 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.

“Viro-Therapy”

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

Figure 16.23 The Biology of Cancer (© Garland Science 2007)

Emergence of Drug Resistance

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?

0 of 90

Physician’s Desk Reference

Oncology Reference Guide203 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, $40,000Average 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 treatmentsOff-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

25 Mar

p. 1548

Ratio of Mortality to Incidence.

If the ratio is large the

prospects for survival are

bleak.

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)

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.