MICaB Course Information

MICa 8004 - Biology of Cancer

Syllabus for MICa 8004 (4 credits)
Spring Semester 2009
MWThF, 9:05-9:55 am
2-120 MCB

Course Coordinator, James McCarthy
2-184 Moos Tower
625-7454
mccar001@tc.umn.edu

The structure of the course is as follows: It is split into distinct topic areas that will be taught by experts in each area. There are 10 subject areas each consisting of 5-7 lecture periods. The lecture periods will include
overviews that are didactic in nature and come from either the required textbook (Weinberg, Cancer Biology), or a recommended text (Bunz, Principles of Cancer Genetics, Springer, copyright 2008 ISBN
978-1-4020-6783-9), or appropriate reviews. The classes will also include a discussion of original research papers that the students in which the students will actively participate.
__________________________________________________________________
The overall objective is to familiarize students with current concepts of cancer initiation, progression, metastasis and therapy.The course has several specific objectives which include more detailed
discussions of:
a. Genetics of Cancer
b. Regulation of Tumor Progression by Translational and
Transcriptional Mechanisms
c. Dysregulation of signal transduction pathways important for
growth and survival
d. Mechanisms of hormonal control in hormonally dependent tumors
e. Importance of the Tumor Microenvironment in tumor formation
and progression
f. Mechanisms of tumor cell survival that facilitate
therapeutic resistance
g. Concepts in tumor immunology that are currently being
considered in therapy
h. Emerging therapies in cancer

___________________________________________________________
The required text is Weinberg, Cancer Biology. We decided it might be considered a financial burden to require too many texts for the course, but I strongly recommend you consider purchasing the Principles of Cancer Genetics book. It is available from the following link: It is available from Amazon.com with free 2 day shipping and no tax for approximately $79.00. This is a 20% discount over the list price.

http://www.amazon.com/s?ie=UTF8&search-type=ss&index=books&field-author=Fred%20Bunz&page=1

You will find this text is an excellent source not only for Cancer Biology, but it also covers basics for genetics in general to put the Genetics of Cancer into the appropriate context.
_________________________________________________________
Examinations in the course will be as follows:
1. There will be an in class quiz administered by each instructor that will cover some of the basic concepts of the topic. The quiz will be short answer in nature and worth a total of 20 possible points.
2. There will also be a take home question given by each instructor handed out at the end of each section. This will be worth 50 points. This question will be designed to give you an opportunity to synthesize
information presented during the discussions and/or design experiments to address specific problems.
Therefore, the point total for the course, will be a possible 700 points. There will be no midterm or final exam.
_____________________________________________________________
The exams are handled electronically. The instructors will send out a take home question by e-mail on the last day of their section and you will send it back to the appropriate instructor by e-mail. You will have one week to complete the take home exam from each instructor.Their e-mail addresses are as follows:

Jaime Modiano (modiano@umn.edu)
Peter Bitterman (bitte001@umn.edu)
Vitaly Polunovsky (polun001@umn.edu)
Amy P.N. Skubitz (skubi002@umn.edu)
Scott Dehm (dehm@umn.edu)
Kaylee Schwertfeger (schwe251@umn.edu)
Carol Lange (lange047@umn.edu)
Haojie Huang (huang253@umn.edu)
Ameeta Kelekar (ameeta@umn.edu)
Chris Pennell (penne001@umn.edu)
Deepali Sachdev (sachd003@umn.edu)
Doug Yee (yeexx006@umn.edu)

My e-mail is (mccar001@umn.edu)

Exams will be turned in to each investigator by using their specific e-mail address.

The class will also have a list serve (mica8004sec2@lists.umn.edu) that will include the registered students, me (mccar001@umn.edu), Louise Shand (shand@umn.edu; MICaB Executive Assistant) and the entire faculty teaching the course.

Faculty will use this e-mail address to contact the entire class, and students can ask specific questions via this list serve on concepts discussed, questions about exams, etc.The list serve will be used by faculty to answer these questions so that everyone may be benefit from the discussion/questions.

January 21 - January 29
Section 1: Modiano; Genetics of Cancer
Powerpoint slides
1. Genetics of cancer at the population level (overview)
2. Mechanisms of oncogenesis - oncogenes, tumor suppressor genes, apoptosis, immortalization, aneuploidy and genetic instability, angiogenesis (overview and discussion of manuscripts)
3. Epigenetics (overview)
4. Genes and environment (overview)
5. Stem cells and cancer (overview and discussion of manuscripts)
6. Animal models - small and large (overview and discussion of manuscripts)

Reading material
Recommended Textbooks -
Bunz, F. Principles of Cancer Genetics. Springer Science 2008: Chapters 1, 2, 3, 4
Weinberg, RA. The Biology of Cancer. Garland Science (Taylor Francis) 2007: Chapters 1 through 13

Recommended (-) and Required (*) Papers:
1.
- Shannon, K. Genetic Predispositions and Childhood Cancer. Environmental Health Perspectives Supplements Volume 106, Number S3 June 1998 - PMID: 9646040
* Ponder BA. Cancer genetics. Nature. 2001 May 17;411(6835):336-41. Review. PMID: 11357140
- Staratschek-Jox A, Shugart YY, Strom SS, Nagler A, Taylor GM. Genetic susceptibility to Hodgkin's lymphoma and to secondary cancer: workshop report. Ann Oncol. 2002;13 Suppl 1:30-3. Review. PMID: 12078899

2.
* Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nat Med. 2004 Aug;10(8):789-99. Review. PMID: 15286780
* Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000 Jan 7;100(1):57-70. Review. No abstract available. PMID: 10647931
- Ferrara N, Kerbel RS. Angiogenesis as a therapeutic target. Nature. 2005 Dec 15;438(7070):967-74. Review. PMID: 1635521
- Pihan G, Doxsey SJ. Mutations and aneuploidy: co-conspirators in cancer? Cancer Cell. 2003 Aug;4(2):89-94. Review. PMID: 1295728
* Sjöblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, Mandelker D, Leary RJ, Ptak J, Silliman N, Szabo S, Buckhaults P, Farrell C, Meeh P, Markowitz SD, Willis J, Dawson D, Willson JK, Gazdar AF, Hartigan J, Wu L, Liu C, Parmigiani G, Park BH, Bachman KE, Papadopoulos N, Vogelstein B, Kinzler KW, Velculescu VE. The consensus coding sequences of human breast and colorectal cancers. Science. 2006 Oct 13;314(5797):268-74. Epub 2006 Sep 7. PMID: 16959974 (PAPER WILL BE DISCUSSED IN CLASS)
* Ley TJ, Mardis ER, Ding L, Fulton B, McLellan MD, Chen K, Dooling D, Dunford-Shore BH, McGrath S, Hickenbotham M, Cook L, Abbott R, Larson DE, Koboldt DC, Pohl C, Smith S, Hawkins A, Abbott S, Locke D, Hillier LW, Miner T, Fulton L, Magrini V, Wylie T, Glasscock J, Conyers J, Sander N, Shi X, Osborne JR, Minx P, Gordon D, Chinwalla A, Zhao Y, Ries RE, Payton JE, Westervelt P, Tomasson MH, Watson M, Baty J, Ivanovich J, Heath S, Shannon WD, Nagarajan R, Walter MJ, Link DC, Graubert TA, DiPersio JF, Wilson RK. DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome. Nature. 2008 Nov 6;456(7218):66-72. PMID: 18987736 (PAPER WILL BE DISCUSSED IN CLASS)

3.
* Egger G, Liang G, Aparicio A, Jones PA. Epigenetics in human disease and prospects for epigenetic therapy. Nature. 2004 May 27;429(6990):457-63. Review. PMID: 1516407
- Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet. 2002 Jun;3(6):415-28. Review. PMID: 12042769

4.
* Hunter DJ. Gene-environment interactions in human diseases. Nat Rev Genet. 2005 Apr;6(4):287-98. Review. PMID: 15803198
- Hemminki K, Lorenzo Bermejo J, Försti A. The balance between heritable and environmental aetiology of human disease. Nat Rev Genet. 2006 Dec;7(12):958-65. Review. PMID: 17139327

5.
* Polyak K, Hahn WC. Roots and stems: stem cells in cancer. Nat Med. 2006 Mar;12(3):296-300. PMID: 1652077
* Barabé F, Kennedy JA, Hope KJ, Dick JE. Modeling the initiation and progression of human acute leukemia in mice. Science. 2007 Apr 27;316(5824):600-4. PMID: 17463288 (PAPER WILL BE DISCUSSED IN CLASS)
* Zhang XB, Beard BC, Trobridge GD, Wood BL, Sale GE, Sud R, Humphries RK, Kiem HP. High incidence of leukemia in large animals after stem cell gene therapy with a HOXB4-expressing retroviral vector. J Clin Invest. 2008 Apr;118(4):1502-10. PMID: 18357342 (PAPER WILL BE DISCUSSED IN CLASS)

6.
- Balmain A. Cancer as a complex genetic trait: tumor susceptibility in humans and mouse models. Cell. 2002 Jan 25;108(2):145-52. Review. PMID: 11832205
* Jónasdóttir TJ, Mellersh CS, Moe L, Heggebø R, Gamlem H, Ostrander EA, Lingaas F. Genetic mapping of a naturally occurring hereditary renal cancer syndrome in dogs. Proc Natl Acad Sci U S A. 2000 Apr 11;97(8):4132-7. PMID: 10759551 (PAPER WILL BE DISCUSSED IN CLASS)
* Lingaas F, Comstock KE, Kirkness EF, Sørensen A, Aarskaug T, Hitte C, Nickerson ML, Moe L, Schmidt LS, Thomas R, Breen M, Galibert F, Zbar B, Ostrander EA. A mutation in the canine BHD gene is associated with hereditary multifocal renal cystadenocarcinoma and nodular dermatofibrosis in the German Shepherd dog. Hum Mol Genet. 2003 Dec 1;12(23):3043-53. Epub 2003 Oct 7. PMID: 14532326 (PAPER WILL BE DISCUSSED IN CLASS)

January 30 –February 11
Section 2: Polunovsky/Bitterman; Translational Control of Tumor Growth
Powerpoint slides
FRI 1/30: BITTERMAN: LECTURE – HALLMARKS OF CANCER
Assigned reading:
• Weinberg, RA. The Biology of Cancer. Garland Science (Taylor Francis) 2007: Chapter 2
• Hanahan D and Weinberg RA. The Hallmarks of Cancer. Cell. 2000, 100:57-70

MON 2/2: POLUNOVSKY: LECTURE - EUKARYOTIC CELL CYCLE
Powerpoint slides
Assigned reading:
• Weinberg, RA, The Biology of Cancer 2007: Chapter 8
Supplemental reading:
• Sherr Ch. and Roberts JM. CDK inhibitors: Positive and negative regulators of cell cycle progression. Genes and Dev, 1999, 13, 1501-1512
• Massague J. G1-cell cycle control and cancer. Nature 2004, 432: 298-306

WED 2/4 BITTERMAN/POLUNOVSKY: DISCUSSION - TUMOR SUPPRESSORS
10 min in class quiz (20 points)
Powerpoint slides
Assigned reading:
• Weinberg, RA, The Biology of Cancer 2007: Chapter 7
• Harris, Miller, Klein, Worst, Tachibana. Suppression of Malignancy by Cell Fusion Nature, 1969, 223: p.363
• Polunovsky VA, Setkov NA, Epifanova OI. Onset of DNA-replication in nuclei of proliferating and resting NIH-3T3 fibroblasts following fusion. Exp Cell Res. 1983, 146: 377-383.
Supplemental reading:
• Sherr Ch. Principles of tumor suppression Cell, 2004, 116: 235-246

THURS 2/5 BITTERMAN: DISCUSSION - ONCOGENES
Powerpoint slides
Assigned reading:
• Weinberg, RA, The Biology of Cancer 2007: Chapter 4
• Chin L, Tam A, Pomerantz J, Wong M, Holash J, Bardeesy N, Shen Q, O'Hagan R, Pantginis J, Zhou H, Horner JW 2nd, Cordon-Cardo C, Yancopoulos GD, DePinho RA. Essential role for oncogenic Ras in tumour maintenance. Nature. 1999 Jul 29; 400(6743):468-72.

FRI 2/6 POLUNOVSKY: LECTURE - TRANSLATIONAL REGULATION OF TUMOR GROWTH
Powerpoint slides
Assigned reading:
• Sonenberg N. eIF4E, the mRNA cap-binding protein: from basic discovery to translational research Biochem. Cell Biol. 2008, 86: 178-183.
Supplemental reading:
• Averous J, Proud CG. When translation meets transformation: the mTOR story. Oncogene 2006, 25, 6423-6435

MON 2/9 POLUNOVSKY: DISCUSSION - TRANSLATIONAL ADDICTION OF CANCER
Powerpoint slides
Assigned reading:
• Avdulov S, Li S, Michalek V, Burrichter D, Peterson M, Perlman D, ,Manivel JC, Sonenberg N, Yee, D Bitterman P, Polunovsky V. Activation of translation complex eIF4F is essential for the genesis and maintenance of the malignant phenotype in human mammary epithelial cells. Cancer Cell. 2004; 5:553-563.
Supplemental reading:
• Polunovsky VA and Bitterman PB. The cap-dependent translational apparatus integrates and amplifies cancer pathways. RNA Biology. 2006, 3: 10-17

WED 2/11 BITTERMAN/POLUNOVSKY: DISCUSSION – TREATING THE TRANSLATIONAL ADDICTION OF CANCER
Powerpoint slides
Assigned reading:
• Graff JR, Konicek BW, Vincent TM, Lynch RL, Monteith D, Weir SN, Schwier P, Capen A, Goode RL, Dowless MS, Chen Y, Zhang H, Sissons S, Cox K, McNulty AM, Parsons SH, Wang T, Sams L, Geeganage S, Douglass LE, Neubauer BL, Dean NM, Blanchard K, Shou J, Stancato LF, Carter JH, Marcusson EG. Therapeutic suppression of translation initiation factor eIF4E expression reduces tumor growth without toxicity. J Clin Invest. 2007 Sep;117(9):2638-48.PMID: 17786246
Supplemental Reading:
• Konicek BW, Dumstorf CA, Graff JR . Targeting the eIF4F translation initiation complex for cancer therapy. Cell Cycle 2008, 7: 2466-2471

Take home exam emailed after class (50 points; Due by email 5PM on Wed, Feb 18)

February 12-February 20
Section 3: Skubitz; Biomarker Discovery/Validation in Tumors

Required reading: Weinberg class textbook pages 727-732.

February 12 - general overview of biomarkers. Since there are few chapters (or even pages) that deal with
this subject in the class textbook (only pages 727-732), I am recommending the following article as background (not required reading) for Thursday's class.Journal of Proteome Research 2005, 4, 1053-1059, "So, you want to look for biomarkers" by Joshua LaBaer.

February 13 - will deal with gene expression and the recommended reading (not required) for background is: Journal of Pathology 2001, 195:41-52, "Towards a novel classification of human malignancies based on gene expression patterns" by A.A. Alizadeh, D.T. Ross, C.M. Perou, and M. van de Rijn.

February 16 - will be a journal club format in which class participation will go over the following article (required reading): American Journal of Pathology, 2004, 165:397-414, "Differential gene expression in ovarian carcinoma: Identification of potential biomarkers" by K. Hibbs et al.

February 18 - will be a lecture on proteomic techniques for biomarker discovery and the recommended reading (not required) for background is:Molecular & Cellular Proteomics, 5:1772-1786, 2006. "Proteomics of breast cancer: Principles and potential clinical applications" by F. Bertucci, D. Birnbaum, and A. Goncalves

February 19 - will be a journal club format in which class participation will go over the following article (required reading): Cancer Research 64:5882-5890, August 15, 2004, "Three biomarkers identified from serum proteomic analysis for the detection of early stage ovarian cancer" Zhen Zheng, Robert C. Bast, Jr., Yinhua Yu, et al

February 20 - will start off with a 10-minute quiz (no notes/books), followed by a journal club format in
which class participation will go over the following article (required reading):PLOS Medicine December 2008, Volume 5, Issue 12, e232, Ovarian carcinoma subtypes are different diseases: Implications for biomarker studies. by M. Kobel, S.E. Kalloger, N. Boyd, et al.

February 23 – March 4
Section 4: Dehm; Transcriptional Control of Tumor Growth
DehmFeb23-Mar4outline.pdf
Lecture 1
Lecture 2
Lecture 3
Lecture 4
Lecture 5
Weinberg chapters/sections:
1.7
1.8
4.5
6.8
6.10
6.12
8.7
8.9
9.1-9.16
14.5

Required Review Articles:
1. Maston GA. Transcriptional Regulatory Elements in the Human Genome. Annu.
Rev. Genom. Human Genet. (2006) 7: 29-59. PMID 16719718
2. Kouzarides T. Chromatin Modifications and Their Function. Cell (2007)
128: 693-705. PMID 17320507
3. Kim TH. Genome-Wide Analysis of Protein-DNA Interactions. Annu. Rev.
Genom. Human Genet. (2006) 7: 81-102. PMID 16722805
4. Kumar-Sinha C. Recurrent Gene Fusions in Prostate Cancer. Nature Reviews
Cancer (2008) 8: 497-511. PMID 18563191

Recommended Review Articles:
1. Kadonaga JT. Regulation of RNA Polymerase II Transcription by
Sequence-Specific DNA Binding Factors. Cell (2004) 116: 247-257. PMID
14744435
2. Ruthenburg AJ. Multivalent Engagement of Chromatin Modifications by
Linked Binding Modules. Nature Reviews Molecular Cell Biology (2007) 8:
983-994.
3. Meyer N. Reflecting on 25 Years with Myc. Nature Reviews Cancer (2008) 8:
976-990.

Original Research Articles to follow

March 5 – 13
Section 5: Schwertfeger; Tumor Microenvironment .
Reading assignments:
Thursday, March 5:
Lecture: Introduction to the tumor microenvironment, extracellular matrix, and tumor associated fibroblasts.
Required reading: Weinberg Chapter 13 pp. 527-551, Chapter 5 pp. 147-150
Powerpoint Slides

Friday, March 6:
Lecture: Angiogenesis and epithelial-mesenchymal transition
Required reading: Weinberg Chapter 13 pp. 556-580, Chapter 14 pp. 587-614
Powerpoint Slides

Monday, March 9:
Discussion of journal article:
Nolan, DJ et al. “Bone marrow-derived endothelial progenitor cells are a major determinant of nascent tumor neovascularization” Genes and Development 21: 1546-1558, 2007.
Powerpoint Slides

Wednesday, March 11:
Lecture: Inflammation and cancer
Required reading: Weinberg Chapter 13 pp. 551-556, 441-452
Optional but strongly recommended: Coussens, L.M. and Werb, Z. “Inflammation and cancer” Nature 420(6917) 2002, 860-867.
Powerpoint Slides

Thursday, March 12:
Discussion of journal article:
de Visser, KE, Korets, LV and Coussens, LM. “De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent” Cancer Cell 7(5), 411-423, 2005.
Powerpoint Slides

Friday, March 13:
In-class quiz
Discussion of journal article:
Giraudo, E, Inoue, M, Hanahan, D. “An amino-bisphosphonate targets MMP-9-expressing macrophages and angiogenesis to impair cervical carcinogenesis” Journal of Clinical Investigation 114(5), 623-633, 2004.
Powerpoint Slides

March 23-March 30
Section 6: Lange; Signal Transduction in Tumors

Weinberg:
Chapters 5 , 6, 8

Required Reading:

MARCH 23: Lecture: MAPK pathway and signaling specificity
1. Ferrell JE Jr. What do scaffold proteins really do?Sci STKE. 2000 Oct 3;2000 (52):PE1. Review.

2. Ubersax JA and Ferrell JE Jr. Mechanisms of specificity in protein phosphorylation. Nature Reviews 530-541 (2007).

3. Anjum R and Blenis J. The RSK family of kinases: emerging roles in cellular signaling. Nature Reviews Molecular Cell Biology 9 747-758 (2008).

MARCH 25: Kinetics: Strength and Duration of the SIgnal
(Discuss Blenis Lab research papers (#5) in good detail in Class)

4. L. Murphy, J. Blenis. MAPK signal specificity: the right place at the right time. Trends in Biochemical Sciences, Volume 31, Issue 5, Pages 268-275.

5. Murphy LO, MacKeigan JP, Blenis J. A network of immediate early gene products propagates subtle differences in mitogen-activated protein kinase signal amplitude and duration. Mol Cell Biol. 2004 Jan;24(1):144-53.

MARCH 26: Nucleo-cytoplasmic transport in signaling
(Discuss Yoon et. al paper (item #7) in class)

6. James E. Ferrell, Jr. How regulated protein translocation can produce switch-like responses. TIBS 23: 461-465, 1998.

7. Yoon S-O et. al (Blenis lab). Ran-binding protein 3 phosphorylation links the Ras and PI3-Kinase pathways to nucleocytoplasmic transport. Mol Cell 29: 362-375 (2008).

MARCH 27: Setting a signal threshold (Multi-site Phosphorylation)
(Discuss Nash paper (item #9) in class)

8. Deshaies RJ and Ferrell JE Jr. Multisite phosphorylation and the countdown to S phase. Cell 107: 819-822 (2001).

9. Nash et. al (Tyers lab). Multisite phosphorylation of a CDK inhibitor sets a threshold for the onset of DNA replication. Nature 414: 514-521. (2001)

MARCH 30: (Ras signaling in cancer biology)
(Discuss Gupta paper (item #11) in class.)

10. AR Ramjaun and J Downward. Ras and Phosphoinositide 3-Kinase: Partners in Development and Tumorigenesis. Cell Cycle 6:23, 2902-2905, 2007

11. S Gupta et. al (Julian Downward lab). Binding of Ras to PI3K p110a is required for Ras-driven tumorigenesis in mice. Cell 129: 957-968, 2007.

Suggested Further reading and background papers:

(review on the MAPK pathway: better detail & more current than text book)
Roux PP, Blenis J. ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions. Microbiol Mol Biol Rev. 2004 Jun;68(2):320-44.

(MAP Kinase primary literature on kinetic modeling of a 3 kinase cascade)
Huang CY, Ferrell JE Jr. Ultrasensitivity in the mitogen-activated protein kinase cascade. Proc Natl Acad Sci U S A. 1996 Sep 17;93(19):10078-83.

(more strength and duration if you are interested in the original literature)
Leon O. Murphy, Sallie Smith, Rey-Huei Chen, Diane C. Fingar & John Blenis. Molecular interpretation of ERK signal duration by immediate early gene products Nature Cell Biology 4, 556 - 564 (2002)

April 1- April 9
Section 7: Huang; Hormone Responsiveness and Tumor Growth
Wednesday, April 1:
Lecture 1 powerpoint slides
Lecture: Androgen action, prostate development, and prostate cancer
Reading:
1. Matusik RJ et al., Prostate epithelial cell fate. Differentiation 76: 682-698.
2. Weinberg Chapter 2: The nature of cancer.
3. Glass CK, Rosenfeld MG. The coregulator exchange in transcriptional functions of nuclear receptors. Genes Dev. 2000 Jan 15;14(2):121-41.
4. Heemers HV, Tindall DJ. Androgen receptor coregulators: a diversity of functions converging on and regulating the androgen receptor transcriptional complex. Endocr Rev. 28: 778-808, 2007.

Thursday, April 2:
Lecture 2 powerpoint slides
Lecture: Androgen action, prostate cancer progression and treatment
Reading:
1. Feldman BJ and Feldman D. The development of androgen-independent prostate cancer. Nature Rev Cancer, 1: 34-45, 2001.
2. Denmeade SR, Isaacs JT. A history of prostate cancer treatment. Nat Rev Cancer. 2:3 89-96, 2002.
3. Scher HI, Sawyers CL. Biology of progressive, castration-resistant prostate cancer: directed therapies targeting the androgen-receptor signaling axis. J Clin Oncol. 23: 8253-61, 2005.
4. Weinberg Chapter 16: The rational treatment of cancer

Friday, April 3:
Paper discussion: Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R, Rosenfeld MG, Sawyers CL. Molecular determinants of resistance to antiandrogen therapy. Nature Medicine 10: 33-9, 2004.

Monday, April 6:
Paper discussion: Zhu P, Baek SH, Bourk EM, Ohgi KA, Garcia-Bassets I, Sanjo H, Akira S, Kotol PF, Glass CK, Rosenfeld MG, Rose DW. Macrophage/cancer cell interactions mediate hormone resistance by a nuclear receptor derepression pathway. Cell. 2006 Feb 10;124(3):615-29.

Wednesday, April 8:
Paper discussion: Xin L, Teitell MA, Lawson DA, Kwon A, Mellinghoff IK, Witte ON. Progression of prostate cancer by synergy of AKT with genotropic and nongenotropic actions of the androgen receptor. Proc Natl Acad Sci U S A. 2006 May 16;103(20):7789-94.

Thursday, April 9:
Powerpoint slides Lecture 6
Paper discussion:
1. Lin B, Ferguson C, White JT, Wang S, Vessella R, True LD, Hood L, Nelson PS. Prostate-localized and androgen-regulated expression of the membrane-bound serine protease TMPRSS2. Cancer Res. 1999 Sep 1;59(17):4180-4.
2. Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, Sun XW, Varambally S, Cao X, Tchinda J, Kuefer R, Lee C, Montie JE, Shah RB, Pienta KJ, Rubin MA, Chinnaiyan AM. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science. 2005 Oct 28;310(5748):644-8.
3. Tomlins SA, Laxman B, Dhanasekaran SM, Helgeson BE, Cao X, Morris DS, Menon A, Jing X, Cao Q, Han B, Yu J, Wang L, Montie JE, Rubin MA, Pienta KJ, Roulston D, Shah RB, Varambally S, Mehra R, Chinnaiyan AM. Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer. Nature. 2007 Aug 2;448(7153):595-9.

In-class quiz (20 points)
Take home exam (30 points), which will be sent out by email right after this class. Answers must be returned to Haojie Huang by email no later than April 16.

April 10-April 20
Section 8; Kelekar; Apoptosis and Autophagy in Tumors
This module will comprise three didactic lectures (April 10, 13 and 15) and three journal club format discussion periods (April 16, 17 and 20)

1) Weinberg Chapter 9, Pages 325 -356

2) Youle, R.J. and A. Strasser, The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol, 2008. 9(1): p. 47-59.

3) Ashkenazi, A, Targeting death and decoy receptors of the tumour-necrosis factor superfamily. Nature Reviews in Cancer, 2002 2(6): p. 420-430

4) Levine, B. and G. Kroemer, Autophagy in the Pathogenesis of Disease. Cell 2008. 132: p. 27-42

5) Jin, S. and E. White, Tumor Suppression through the management of metabolic stress. Autophagy, 2008, 4(5): p. 563-566

The specific research articles that we will discuss are listed below.
April 16
Kolluri, S.K., X. Zhu, X. Zhou, B. Lin, Y. Chen, K. Sun, X. Tian, J. Town, X. Cao, F. Lin, D. Zhai, S. Kitada, F. Luciano, E. O'Donnell, Y. Cao, F. He, J. Lin, J.C. Reed, A.C. Satterthwait, and X.K. Zhang, A short Nur77-derived peptide converts Bcl-2 from a protector to a killer. Cancer Cell, 2008. 14(4): p. 285-298.

April 17
Wei, Y., S. Pattingre, S. Sinha, M. Bassik, and B. Levine, JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy. Mol Cell, 2008. 30(6): p. 678-688.

April 20
Nicklin, P., P. Bergman, B. Zhang, E. Triantafellow, H. Wang, B. Nyfeler, H. Yang, M. Hild, C. Kung, C. Wilson, V.E. Myer, J.P. MacKeigan, J.A. Porter, Y.K. Wang, L.C. Cantley, P.M. Finan, and L.O. Murphy, Bidirectional transport of amino acids regulates mTOR and autophagy. Cell, 2009. 136(3): p. 521-534.

A 20 point quiz will be administered in the last 15 minutes of the class period on Friday, April 17. The take-home test question/s will be emailed to you by 5:00 PM on Monday, April 20.

April 22-April 30
Section 9: Pennell ; Tumor Immunology
April 22 – Overview of Tumor Immunology and Immunotherapy
Weinberg: Chapter 15 (if students have a background in immunology, skip sections 15.1-15.6 and begin with section 15.7 on p 669).
Powerpoint slides

April 23 – Cancer Immunosurveillance
Stagg J, Johnstone RW and Smyth MJ. 2007. From cancer immunosurveillance to cancer immunotherapy. Immunological Reviews 220:82-101
Powerpoint slides
.
April 24 – Journal club
Guerra N, Tan YX, Joncker NT, Choy A, Gallardo F, Xiong N, Knoblaugh S,
Cado D, Greenberg NR, and Raulet DH. 2007. NKG2D-Deficient Mice Are Defective in Tumor Surveillance in Models of Spontaneous Malignancy. Immunity 28:571-580.
Powerpoint slides

April 27 – Immune regulatory subsets
Chaput N, Conforti R, Viaud S, Spatz A, and Zitvogel L. 2008. The Janus face of dendritic cells in cancer. Oncogene 27:5920-5931.
Powerpoint slides

April 29 – Journal club
Curtin JF, Candolfi M, Fakhouri TM, Liu C, Alden A, Edwards M, Lowenstein PR and Castro MG. 2008. Treg Depletion Inhibits Efficacy of Cancer Immunotherapy: Implications for Clinical Trials. PLoS ONE 3(4): e1983.
Powerpoint slides

April 30 – Antibody-based therapy/Journal club
Stagg J, Sharkey J, Pommey S, Young R, Takeda K, Yagita H, Johnstone RW and Smyth MJ. 2008. Antibodies targeted to TRAIL receptor-2 and ErbB-2 synergize in vivo and induce an antitumor immune response. Proc. Natl. Acad. Sci. USA 105(42):16254-16259.
Powerpoint slides

May 1- May 8
Section 10: Sachdev/Yee; Emerging Therapies for Cancer Treatment

The first two sessions will be didactic lectures. The following three sessions will be interactive discussions of papers listed below. Students are expected to participate in these discussions.

Assigned reading for this module includes Weinberg Chapter 16 pp. 725-737; 748-75; 765-769 and the required papers listed below:

Friday, May 1
Introductory lecture on targeted therapies for cancer.
Powerpoint slides

Monday, May 4
Lecture on overview of resistance to endocrine therapies.
Powerpoint slides

Suggested reading: (This is for your information only and if you wish to read more on this topic)

Ring A, Dowsett M. Mechanisms of tamoxifen resistance. Endocr Relat Cancer. 2004 Dec;11(4):643-58.

Arpino G, Wiechmann L, Osborne CK, Schiff R. Crosstalk between the estrogen receptor and the HER tyrosine kinase receptor family: molecular mechanism and clinical implications for endocrine therapy resistance. Endocr Rev. 2008 Apr;29(2):217-33.

Iorns E, Turner NC, Elliott R, Syed N, Garrone O, Gasco M, Tutt AN, Crook T, Lord CJ, Ashworth A. Identification of CDK10 as an important determinant of resistance to endocrine therapy for breast cancer. Cancer Cell, 13(2):91-104, 2008.

Wednesday, May 6
Discussion of the paper by Massarweh et al. in Cancer Res.
Powerpoint Slides

Required reading:
Massarweh S, Osborne CK, Creighton CJ, Qin L, Tsimelzon A, Huang S, Weiss H, Rimawi M, Schiff R. Tamoxifen resistance in breast tumors is driven by growth factor receptor signaling with repression of classic estrogen receptor genomic function. Cancer Research, 68(3):826-33, 2008.

Be prepared to discuss the paper in class.

Thursday, May 7
We will discuss the paper by Guix et al.
Powerpoint Slides

Required reading:
Guix M, Granja Nde M, Meszoely I, Adkins TB, Wieman BM, Frierson KE, Sanchez V, Sanders ME, Grau AM, Mayer IA, Pestano G, Shyr Y, Muthuswamy S, Calvo B, Krontiras H, Krop IE, Kelley MC, Arteaga CL. Short preoperative treatment with erlotinib inhibits tumor cell proliferation in hormone receptor-positive breast cancers. J Clin Oncology, 26 (6):897-906, 2008.

Recommended/Suggested Additional Reading:
The paper by Smith et al. below will serve as background for discussing the Guix et al paper and you are encouraged to read it.

Smith IE, Walsh G, Skene A, Llombart A, Mayordomo JI, Detre S, Salter J, Clark E, Magill P, Dowsett M. A phase II placebo-controlled trial of neoadjuvant anastrozole alone or with gefitinib in early breast cancer. J Clin Oncology, 25(25):3816-22., 2007.

Kummar S, Kinders R, Rubinstein L, Parchment RE, Murgo AJ, et al. Compressing drug development timelines in oncology using phase '0' trials. Nature Reviews Cancer 7, 131 - 39 (01 Feb 2007), doi: 10.1038/nrc2066, Perspective

Be prepared to discuss the Guix et al. paper in class.

Friday, May 8
Discussion of the paper by Pàez-Ribes et al.
Powerpoint Slides

Required reading:
Pàez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Viñals F, Inoue M, Bergers G, Hanahan D, Casanovas O. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell. 2009 Mar 3;15(3):220-31.

Recommended reading:
Loges S, Mazzone M, Hohensinner P, Carmeliet P. Silencing or fueling metastasis with VEGF inhibitors: antiangiogenesis revisited. Cancer Cell. 2009 Mar 3;15(3):167-70.

The article by Loges et al. is a minireview that discusses how VEGF inhibitors can induce divergent effects on primary tumor growth and metastasis which is the topic of the paper to be discussed in class.

Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, Kerbel RS. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell, 2009 Mar 3:15(3):232-239.

This is another report in the same issue of Cancer Cell about sunitinib, a VEGFR kinase inhibitor accelerating metastasis during short-term therapy.

Be prepared to discuss the paper by Pàez-Ribes et al. in class.

Quiz and take home exam

A 15 minute in-class quiz worth 20 points will be given at the end of the class on Thursday, May 7 or at the beginning of class on Friday, May 8.

A take home exam worth 50 points will be sent via e-mail by 5 pm on Friday, May 8. Please return the exams to Deepali Sachdev via email (sachd003@umn.edu) by 5 pm on Friday, May 15.