Lecture #25 | Treatment of cancer

After prevention, what is the next best thing?

Detection

• the disease is present but can be detected in stains or through X-rays

• key is early detection and screening

Mechanisms of conventional chemotherapy

1. Inactivate DNA-blocks DNA/RNA synthesis through alkylating agents like crosslink DNA and antibiotics

2. Inhibit DNA synthesis through antimetabolites (interfere w/ DNA polymerase by blocking purine/pyrimidine synthesis) or etoposide which inhibits topoisomerase

3. Inhibit metaphase through vinca alkaloids by binding tubulin, interfering with spindle formation

Problem with conventional chemotherapy

1. Not very selective

   1. harms normal cells too

   2. mechanisms are specific to replicating cells; not just tumor cells

   3. side effects in normal replicating cells

2. serious side effects but bot always effective

   1. can kill patient

   2. needs to be given in increment too allow pt to recover

   3. not all tumor cells are replicating and hence would not be killed

3. 30% of all pts un dergoung chemo develop resistance

4. Problem with efficacy

   1. Effective against certain like leukemias (juvenile)

   2. Not effective against most common adults

   3. works well temporarily

5. Problems with delivery

   1. Often <1% of a drug reaches its target

   2. Therapeutic window that is often very narrow is the difference between the minimum effective dose and maximum tolerated dose

Mechanisms of resistance to chemo drugs

1. Resistance to DNA damaging drugs

   1. Cells lose ability to apoptoses

2. Resistance to a single drug

   1. amplification of the DHFR gene leads ro resistance to methotrexate

3. Resistance to multiple drugs (MDR)

   1. Tumor cells resistant to one drug are often resistant to others

   2. amplification of the MDR-1 gene

      1. encodes a membrane spanning ATPase pump and pumps the drugs and other molecules in and out of the cell

MDR-1 gene

Encodes an ATPase pump that is often over expresses in cancers treated with chemotherapeutic agent

• small molecule pump that undergoes a conformational change upon substrate binding, followed by ejecting the substrate out of the cell

• abundant in liver, intestines and kidney

New advances in chemo

1. Newly identifies compounds from nature can show potent anti-cancer effects like Taxol (Pacific yew tree) which acts by inhibiting microtubule depolymeraziation to treat ovarian and breast cancer

2. New combo of old drugs like treat treat cancer with tamoxifen and taxol (typically treats ovarian cancer)

3. New methods to deliver drugs

   1. Liposomes (spherical vesicle made up of phospholipid bilayer to carry drugs in different ways

Anti-cancer compounds from nature

• Epothilone A (mycobacteria) which inhibits microtubule depolarization (30x more stable than taxol)

• Bryostatins (marine animal bryozoans) which binds PKC and blocks its activity → treats leukemia

• Vinblastine and vincristine (periwinkle): used to create Hodgkin’s diseases and childhood leukemia

Why is it important to preserving natural environment for cancer?

Nature took billions of years to develop complex chemicals that we would have not thought was possible

• 50% of the most prescribed medicines in the US contain compounds derived from nature

Immunotherapy

Any therapy that makes use of the immune system

1. Monoclonal antibodies (Ab): recognize a single antigen: are completely specific

   1. Herceptin→ Ab against Her2 receptor (epidermal growth factor receptor)

      1. over expressed in 30% of breast cancer

2. Tumor Vaccines: Gene therapy to activate immune system

   1. ex vivo → remove tumor cell from pt add DNA to express a gene to activate immune system

3. Adoptive cell transfer of anti-tumor lymphocytes

   1. Amplify ex vivo tumor infiltrating lymphocytes from Timors and reinfect into patient after partial ablation of bone marrow

CAR T-cell therapy

Makes use of T cells natural ability to recognize and kill tumor cells

• genetically engineering a patients own T cells to attack cancer cells

Strategy for CAR T-cell therapy

1. collect blood

2. isolate cells

3. stimulate t-cell proliferation

   1. genetically engineered to contain Ig variable domain specific to the tumor ag fused to cytoplasmic domains to signal to initiate apoptosis pf tumor cell

4. transfection

5. transfuse into patient

Limitations and progress of CAR T cells

1. Lacks appropriate tumor-specific antigens on solid tumors

2. can induce Cytokine release syndrome to supercharge the inflammatory response

Progress

• Most effective B cell lymphomas and leukemias

• Works for certain brain cancers

Rational drug treatment

The scientific and evidence based approach to prescribing mediations to ensure a patient receives the right drug in the correct dose for an appropriate duration at an affordable cost

• antiangiogenic drugs show that they are the most effective combo with conventional chemotherapy

• Designer drugs

  • Iressa: antagonizes the action. of mutant EGFR by binding to the ATP binding site in the kinase domain

    • Specific to the mutates form of EGFR

    • Radically shrinks lung tumors that are resistant to traditional chemo but resistant tumor cells can evolve that have additional mutations

  • Valcade: proteasome inhibitor, leads to suppression of NFkB pathway by blocking degradation of IkB. MFkB activates cell proliferation genes as well as anti-apoptoisis genes