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A Phase II Study Of Tetrathiomolybdate, An Anti-Angiogenic Agent, In Women With Breast Cancer At High Risk Of Relapse
Background: Breast cancer (BC) recurrence risk is proportional to tumor size and number of lymph nodes(LNs) involved at time of diagnosis. Stage 4 BC is considered an incurable disease even if a complete remission with chemotherapy is obtained (Stage 4 NED). There are few additional treatment options after completion of adjuvant therapy for high-risk patients(pts). For pts who are Stage 4 NED there is no standard treatment approach. It is hypothesized that relapse in both situations is a direct result of sub-clinical occult disease. As relapse is associated with activation of an angiogenic switch, the consensus opinion is that if anti-angiogenesis strategies are to be effective, they will need to be utilized in a minimal residual disease state environment (ie. no overt disease). Copper is an essential co-factor in the angiogenic process hence one approach has been to induce a relative copper-deficient state as an anti-angiogenic strategy. Preclinical and phase I data suggest that tetrathiomolybdate (TM), an oral anti-copper agent used in Wilson’s disease, might be an effective approach in reducing both overt and sub-clinical tumor load. Objective/Hypothesis: 1.Copper stores will be safely depleted to the level that cellular function can take place but tumor neo-angiogenesis will be impaired. 2.TM will decrease the number of pro-angiogenic marrow derived endothelial and hematopoietic progenitors and overall plasma angiogenic activity. Specific Aims: 1.To assess the safety and tolerability of tetrathiomolybdate in pts with BC at high risk of tumor recurrence. 2.To evaluate the effect of tetrathiomolybdate on the circulating surrogate markers of angiogenesis Study Design: Phase II trial of TM in 50 BC pts at high risk of recurrence. Eligible pts include those with greater than 4 LNs involved with cancer and Stage 4 BC NED. Pts would orally ingest TM daily for 2 years. They would be evaluated with physical exam and routine laboratory studies on a monthly basis. Imaging studies would be performed every 4 months. Second, we will evaluate circulating surrogate markers of angiogenesis at baseline, one month and every 6 months for the duration of the trial. All of this work will be performed in the laboratory of Dr. Shahin Rafii. Plasma angiogenic activity will be evaluated several ways including a plasma angiogenic assay and assessment and quantification of circulating endothelial and pro-angiogenic hematopoietic progenitor cells. This includes: (1) quantification of number of circulating CD133+VEGFR2+, CD34+VEGFR2+, CD133+CD146+, CD133+CD105+, CD133+CD34+ endothelial progenitors and VEGFR1+ pro-angiogenic hematopoietic cells and CD133+VEGFR3+ (lymphangiogenic progenitor cells) performed by flow cytometry (2) Quantification of VEGFs (A,B,C,D) and PlGF by western blot and ELISA (3)Apoptotic status of circulating progenitors (TUNEL) and level of activation (ICAM-1, VCAM-1,E-selectin) (4)The overall plasma angiogenic activity will be evaluated using an in vitro functional assay by culturing aliquots of patient’s plasma with cultured human umbilical vein endothelial cells (HUVECs). Potential Outcomes: The prevention of the “angiogenic” switch could prolong tumor dormancy indefinitely which would result in an increased cure rate.
Breast cancer recurrence risk increases with increasing tumor size and number of lymph nodes involved with cancer at the time of diagnosis. Stage 4 breast cancer is considered an incurable disease even if a complete remission with chemotherapy is obtained (also called Stage 4 with no evidence of disease or Stage 4 NED). There are few additional treatment options after completion of adjuvant therapy for the moderate and high-risk patients. For patients who are Stage 4 NED there is no standard treatment approach. The observation that has always puzzled researchers is why a patient can relapse with cancer after many years of being cancer-free. Similarly, in patients whose cancer has spread, why can a treatment that removes all visible traces of breast cancer recur again? Multiple lines of evidence point to the fact that cancer cells lie dormant awaiting for a “signal” to start growing. It is believed that a crucial part of this “signal” is the ability to recruit blood vessels to the dormant tumor cell so that it can lay down blood vessels to feed itself and spread. This signal has been termed the “angiogenic switch”. There are many compounds being tested that might affect the turning on of this “angiogenic switch”. These are called anti-angiogenesis agents. It is well known that copper plays an essential role in the angiogenic process hence anti-copper strategies have been employed to try to halt this process. Experiments in laboratory animals and people with advanced cancer support this concept. In our study, we propose to study the effects of a copper-reducing compound, tetrathiomolybdate (TM), on the pro-angiogenic factors we believe are important in this process. Our study will be conducted in fifty women with breast cancer who have completed standard treatment but because of their high risk of recurrence are looking for additional experimental treatment options. Women who are eligible for this trial must have at least 4 lymph nodes affected by breast cancer and have no overt evidence of cancer (includes Stage 4 NED). They will ingest TM pills daily for two years. We hypothesize that TM will reduce these blood vessel stimulating factors so that the “angiogenic switch” never gets turned on. Over the course of the study, they will have imaging studies and physical exams to evaluate their cancer status. Second, we will evaluate angiogenic markers in the blood that we believe might affect the activation of this “angiogenic switch”. We will measure these before TM therapy, at one month and every 6 months for the duration of the trial. Plasma angiogenic activity will be evaluated several ways including a plasma angiogenic assay (HUVEC co-cultured with patient plasma and evaluated with a functional grading schema) and assessment and quantification of circulating endothelial and pro-angiogenic hematopoietic progenitor cells by flow cytometry and TUNEL assay. Plasma VEGF-A, VEGF-C, VEGF-D, Thrombospondin-1, histidine-rich glycoprotein will be evaluated at the same time points. We hypothesize that TM will decrease the number of pro-angiogenic marrow derived endothelial and hematopoietic progenitors and overall plasma angiogenic activity. This type of research is targeting a group of patients we know are at high risk of relapse, ie. high risk of having dormant cancer cells. We believe that we will be able to prevent the “angiogenic” switch from being turned on and for the angiogenic cascade to start. We also believe that we will identify predictors in the blood that herald a relapse and if so, can target it with a treatment such as the one described.