CB 399 Targeting signal transduction pathways for drug discovery: focus on breast cancer Spring 2010

Intellectual Unit:

Targeting signal transduction pathways for drug discovery: focus on breast cancer

Course lecturers: Nancy Lin MD, PhD (DFCI); Daniel Silver MD, PhD (DFCI), Ian Krop MD, PhD (DFCI) and Michele Sanicola PhD Biogen
Course Organizer: David Frank MD, PhD (DFCI) and Catherine Dubreuil PhD, Catherine_Dubreuil@hms.harvard.edu
Curriculum Fellow: Johanna Gutlerner, Johanna_Gutlerner@hms.harvard.edu

With our increased understanding of the molecular events underlying breast cancer pathogenesis, new opportunities arise to develop treatment strategies to exploit these molecular insights. However, many hurdles stand between laboratory advances and treatments that can help patients.  Focusing on both key cellular mechanisms as well as a range of pharmacological strategies, this course will examine how basic knowledge in cancer biology can inform the development of rational approaches for the treatment of breast cancer.  Among the targets to be considered are kinase cascades, DNA repair processes, and cell surface proteins.  Therapeutic strategies utilizing both small molecules and antibodies will be addressed. The central theme will be how a basic understanding of tumor biology can be translated into clinically relevant strategies, and insight will be provided from experts in translational science, clinical research, and industry-based drug development.

First Meeting: April 7th 12:30 – 4:30 pm
Location: TMEC Bldg., room 227

Second Meeting:  April 12th 1 – 3:30 pm.
Location: TMEC Bldg., room 333


Second Unit: student assignment:

Choose ONE of the following to discuss:

1. Antibodies are often used as therapeutic agents to specifically target proteins that promote tumorigenic cell properties.  Antibodies can block activities or stimulate activities depending on the situation.  For oncology, antibodies can also be armed or conjugated with potent cytotoxics to deliver a lethal payload to the cell.  Several interesting oncology targets include the cell adhesion molecule, EpCam ; the collagen receptor DDR1 ; and the insulin like growth factor receptor, IGFR1 .  Pick one of these targets and address whether it would make a good target for a 'naked' antibody approach, an antibody drug conjugate approach or could it be targeted in both ways.

2. Discuss the issue of resistance to agents targeting defective DNA repair. Does the concept of “ addiction “ apply?

3. Discuss the challenges, advantages and disadvantages in “broad trials (including all breast cancer subtypes)” versus specific trials (including just one subtype or enriched for one target)

4. For Her2 talk. We are just starting to study the PI3Kinase inhibitors in the clinic.

1)    Discuss how we might determine what tumor characteristics predict responsiveness or resistance to this new therapy (using data and tissue samples from the trials) so that we could tailor the use of these agents to patients most likely to benefit.
2)    Even if PI3Kinase inhibitors work well, tumors are likely to eventually develop resistance. How could we use trials and tissue results to indentify resistance mechanisms?

Assigned Readings (files attached for registered users):

Ricart, AD and Tolcher, AW (2007) Technology Insight: Cytotoxic Drug Immunoconjugates for Cancer Therapy. Nature Clinical Practice, 4:4, pp. 245 – 255.

Turner, N, et al (2004) Hallmarks of ‘BRCAness’ in Sporadic Cancers. Nature Reviews Cancer, 4, pp 1-6.

Sorlie, T, et al (2001) Gene Expression Patterns of Breast Carcinomas Distinguish Tumor Subclasses with Clinical Implications. PNAS 98:19,pp 10869—10874.

Strizzi, L (2005) Cripto-1: A Multifunctional Modulator During Embryogenesis and Oncogenesis.  Oncogene 24, pp. 5731-5741.

Senter, PD (2009) Potent Antibody Drug Conjugates for Cancer Therapy. Current Opinion in Chemical Biology 13 pp. 235-244.

Spector, NL, and Blackwell, KL (2009) Understanding the Mechanisms Behind Trastuzumab Therapy for Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer.  Journal of Clinical Oncology, 27:34, 5838—5847.