The History of Cancer and Its Treatments

1. The History of Cancer and Its Treatments Osher Lecture 4 May 1, 2013 Breast Cancer as a Model System Russell Doolittle, PhD

2. Here are two videos to check out dealing with topics we have covered already: Video of fertilization of frog eggs: google “video frog egg fertilization” A YouTube presentation by Linda Runft will be among the top hits. Video of DNA being wrapped and compacted: http://apod.nasa.gov/ Click on “Archive” and then select August 21, 2012 (courtesy of class member)

3. Responses and repairs to questions after lecture 3. About the possibility of being infected with a cancer virus during routine vaccination (e.g., during a flu shot). Regarding saliva tests for determining risk factors for cancer A missed opportunity for associating a chromosomal abnormality, a hyperactive kinase, a cancer, a drug, and a recent patent ruling.

4. About the possibility of being infected with a cancer virus during routine vaccination (during a flu shot, e.g.) It was found in the late 1950’s that recipients of the Salk polio vaccine had been incidentally infected with a virus called SV40. After the break I plan to say a few more words about this and other claims of inadvertent transmissions, etc.

5. Regarding saliva tests for determining risk factors for cancer $99 (More coming up shortly about breast cancer.)

6. The Philadelphia chromosome: the result of a translocation involving two “oncogenes” In the late 1950’s, two researchers noticed that in one kind of leukemia (CML), one of the smaller chromosomes was missing a piece at one end. In 1973 another researcher meticulously examined chromosome spreads from many persons with CML and found the missing piece at the end of another chromosome. These were chromosomes 22 and 9. By chance the tips of these chromosomes encoded proto-oncogenes. One was a gene (Bcr) th presence of which made the other, a kinase, called c-Abl, hyperactive. The fusion of these two genes is known as Bcr-Abl. This fusion protein also interferes with the activity of a tumor suppressor, making it even more aggressive. Bcr-Abl is uniquely inhibited by Gleevec, an effective chemo agent for CML, and the subject of a recent patent ruling in India .

7. Gleevec (STI571)

8. Breast Cancer as a Model It is estimated that in 2013, 230,000 women in the USA will be diagnosed with breast cancer. There will be approximately 40,000 deaths. Estimates are that 10-20% of women in the USA will get breast cancer during their life time. It is estimated that 10-15% of those who get breast cancer have an identifiable genetic pre-disposition. The frequency varies with ethnicity; as many as 1% of Ashkenazi Jewish women have a particular mutation in the BRCA2 gene.

9. Breast cancer is cancer that starts in the tissues of the breast. There are two main types of breast cancer: * Ductal carcinoma starts in the tubes (ducts) that move milk from the breast to the nipple. Most breast cancers are of this type. * Lobular carcinoma starts in the parts of the breast called lobules, which produce milk. In rare cases, breast cancer can start in other areas of the breast.

11. Treatments for Breast Cancer Surgery Radiation Chemotherapy Hormone therapy Targeted therapy

12. Surgery History: Queen Atossa (ca 500 BCE) to Halsted (1890’s) (Herodotus tells a better story here than Mukerjee) In 1865 Joseph Lister successfully removed a cancerous breast from his sister: ether, carbolic acid and a dining table. Halstead (1890’s) was a radical! Current surgeries: Lumpectomy Partial mastectomy Total mastectomy Modified radical mastectomy

13. Radiation X-rays discovered in 1895. Within five years being used to attack solid tumors. Current uses: Direct extermal beam at solid tumors. Radioactive sources implanted in tumor region. Radiation (including mammograms) can cause tumors. It’s use is a matter of risk/benefit calculation.

14. Chemotherapy Adjuvant chemo: often a follow-up to surgery or radiation. C-M-F regimen. C = cytoxin (nitrogen mustard) M = methotrexate (like aminopterin) F = fluorouracil Some other chemo agents: taxol (paclitaxol) slows cell division by binding to microtubules. Cis-platinate: binds to DNA and cross-links the strands, preventing DNA replication.

15. Hormone Therapy The majority of breast cancers are estrogen-dependent Estrogen (a hormone) is made in the ovary. There are different ways of treating these cancers: e.g., there are estrogen look-alikes that can bind to the estrogen-receptor, and there are chemicals that can inhibit the natural formation of estrogen

16. The amounts of estrogen in the circulation vary greatly during a woman’s life and especially during pubescence (menarche), pregnancy, lactation and menopause.

18. Estrogens vary greatly during and after pregnancy.

19. Hormone Therapy As noted, many breast cancers are sensitive to the hormone estrogen that causes the breast cancer tumor to grow. Such cancers have estrogen receptors in their cells making them estrogen receptor-positive cancer or ER-positive cancer.

21. Raloxifene (binds to estrogen receptor)

22. Tamoxifin and raloxifene block the binding of estrogen by the estrogen receptor.

23. Estrogen signaling pathway leading to changed gene expression.

24. Herceptin: an Example of Immunotherapy Some women have HER2-positive breast cancer. HER2 refers to “human epidermal growth factor receptor”gene that makes a protein that helps cells grow, divide, and repair themselves. When cells (including cancer cells) have too many copies of this gene, they grow faster. Antibodies targeted to the protein can slow the process. Herceptin is such an antibody.

25. Risk Factors and Genetic Characteristics for Breast Cancer Family history, inherited mutations, early menarche, reproductive experience (recall the nuns), age. BRCA1, BRCA2: 5-10% of women with breast cancer have germ-line mutations for one of these genes These two genes were patented in 1994 and 1995 by Myriad Genetics. The patents are currently being challenged before the US Supreme Court.

26. More about BRCA-1 and BRCA-2 Myriad Genetics offers tests for these two genes at $3,000 per pop. Over a million of these tests have been performed (gross $3 billion)

27. Many women with genetically damaged BRCA-1 or BRCA-2 are opting for prophylactic breast removal. This year Allyn Rose, a 24-year old Miss America contestant, announced that on the day after the contest she would be having both her breasts removed. Even women with lesser risk are being urged to take tamoxifen or Raloxifene prophylactically, side effects aside.

28. What do the BRCA-1 and BRCA-2 genes code for? The short answer is they help repair DNA. They are also what is known as “caretaker genes.” In lecture 5 we will be distinguishing caretaker from gatekeeper genes (and their products). We will also be considering driver mutations and passenger mutations.

29. DNA RNA Protein Mistakes in DNA replication are reflected in protein structure. There are many different kinds of mistake that occur in DNA replication: simple base substitutions deletions unequal crossing over breakage and reunion in general, including translocations

30. DNA RNA Protein DNA is composed of 4 kinds of unit: A, G, C, T. RNA is composed of 4 kinds of unit: A, G, C, U. proteins are composed of 20 kinds of unit: amino acids A triplet code (three units of DNA or RNA) is necessary to distinguish 20 amino acids. For example, AAA (DNA) is transcribed as UUU, which is translated as the amino acid phenylalanine. If one of the units in the DNA is mutated, e.g., AAA -> ATA, This will be transcribed as UAU, which is translated as the amino acid tyrosine.

32. Four things taken three at a time = 43 =64 The code is redundant. Most amino acids have more than one codon. Synonymous mutations base substitution gives rise to same amino acid Non-synonymous mutations base substitution gives rise to different amino acid The ratio of non- synonymous mutations to synonymous ones is an index of non-random survival.

33. Numbers of non-synonymous mutations per cell line colorectal lung melanoma colorectal breast AML CLL ALL

35. Are humans special? Chimpanzees (and other primates) get much less breast cancer. Chimpanzees (and other primates) don’t delay child bearing. Chimpanzees (and other primates) don’t experience menopause.