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Recent Scientific Progress and Achievements:
New Therapeutic Targets and Approaches

Accomplishments since the last renewal have focused on identification of therapeutic targets and on development of new drugs including targeted and non-targeted liposomal small molecules or nucleic acids. These include:

• Demonstration by Drs. Moasser (a new recruit to the Cancer Center) Kevan Shokat (Cell Cycling and Signaling Program) and Byron Hann (Preclinical Therapeutics Core) and colleagues that HER3 and consequently PI3K/Akt signaling evade inhibition by current HER family TKIs in vitro and in tumors in vivo (Sergina et al. 445; 437-41, 2007).
• Illustration by Drs. Balmain, Gray and colleagues that normal tissues from p53-/- mice have increased Aurora-A protein levels, but lymphomas from these mice exhibit heterozygous deletions of Aurora-A and/or reduced protein expression (Mao et al. 11; 161-73, 2007).
• Development by Drs. Park, Marks, and Benz (member before leaving UCSF), of a self-assembling nucleic acid-lipid nanoparticle suited for targeted gene therapy (Hayes et al. 13; 646-51, 2006).
• Continued development by Dr. Francis Szoka and colleagues a therapeutic agent comprising doxorubicin (DOX) conjugated to a biodegradable asymmetric polyester dendrimer (Lee et al. 103; 16649-16654, 2006).
• Identification by Dr. Ira Goldfine and colleagues of e diaryl urea compound, PQ401, as a potent inhibitor of IGF-IR signaling (Gable et al. 5; 1079-86, 2006).
• Demonstration by Drs. Andrei Goga and Benz (member before leaving UCSF) and colleagues that infection of ERBB2 expressing cell lines with the miRNAs, miR-125a and miR-125b suppress both ERBB2 and ERBB3 thereby impairing anchorage-dependent growth and reducing migration and invasion capacities(Scott et al. 2006).
• Continued development by Drs. Esserman, Hylton of the The I-SPY TRIAL, (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging And moLecular Analysis), a multi-center trial of serial imaging and biopsy for women with tumors at least 3 cm in size who undergo neoadjuvant chemotherapy.
• Development by Dr. Rugo of a collaboration with Dana-Farber and Indiana University focusing on a phase II pilot study of bevacizumab alone and bevacizumab plus metronomic chemotherapy for patients who are identified as high risk following neoadjuvant therapy (based on residual cancer at the time of surgical resection)..
• Participation by Drs. Bevan and Alvarado, of a multi-institutional international randomized trial (TARGiT) designed to test whether a single intraoperative dose of radiation therapy (RT) is as good as five to six weeks of standard external beam RT.
• Development by Dr. Melisko of several trials for women with brain metastases that have progressed following radiation. These include a phase II trial of irinotecan and temozolomide as well as a phase II trial of lapatinib in HER2+ leptomeningeal disease.
• Recurrent chest wall disease is another difficult clinical scenario because of the lack of good options for treatment. Drs. Park and Sneed conducted an investigator-initiated pilot trial of doxil and hypothermia for metastatic breast cancer to the chest wall. Twenty-eight women were treated on study, four patients had a complete response, and ten had a partial response. Sequential hypothermia plus liposomal doxorubicin significantly increase drug delivery and improves antitumor efficacy in patients with metastatic breast cancer without increasing toxicity.
• Development by Dr. Christine Miaskowski (Society, Diversity and Disparities Program) of two efforts to document symptoms following surgery, specifically neuropathic pain and lymphedema. Drs. Ewing and Rugo are co-investigators on this trial and UCSF is the dominant accrual site. Dr. Melisko and colleagues are conducting a trial of a vaginal estrogen ring compared to testosterone cream for vaginal symptoms and will also measure serum estradiol levels. Dr. Rugo, in collaboration with LBNL, has opened a prospective a NCI-funded longitudinal study using PET and MRI of the brain and serial cognitive function testing to measure changes in cognitive function before and after chemotherapy, including up to 18 months following completion of chemotherapy.

Future Plans: We will develop a multi-institutional consortium that will develop gene specific, RNAi-based anticancer therapies to advance human cancer treatment. We will develop several next generation neoadjuvant trials (I-SPY TRIAL) targeting DCIS or locally advanced cancers that will test our ability to perform genomic triage, and to use molecular imaging to further triage patients, based on actual response.