A phase II study of copper-depletion using tetrathiomolybdate (TM) in patients (pts) with breast cancer (BC) at high risk for recurrence: Updated results.

Abstract

2557 Background: The tumor microenvironment (TME) plays a critical role in the spread of tumors. Bone marrow derived VEGFR2+endothelial progenitor cells (EPCs) and copper-dependent lysyl oxidase (LOX) are key in tumor progression. We hypothesized TM-associated copper depletion inhibits tumor metastases by reducing the number of EPCs and other copper dependent (CD) processes in the pre-metastatic niche. These results are an update with longer follow-up. Methods: Phase II study of BC pts at high risk for recurrence, defined as node+ triple negative (TNBC), stage 3 and 4 with no evidence of disease (NED) were enrolled on a trial of CD with TM. Ceruloplasmin (Cp) levels were maintained between 8-16 mg/dl for two years with an extension phase or until relapse. The primary endpoint was change in EPCs measured by flow cytometry before and during treatment. Secondary endpoints included tolerability, safety, PFS and LOXL-2 levels. Results: 75 pts received 2650 cycles of TM on primary and extension study. The median age is 51 years (range 29-66). Forty-five pts have stage 2/3 BC and 30 with stage 4 NED. TNBC pts were 48% and 40% of pts are stage 4 NED. Median Cp level decreased from 28 to 16 (p < 0.0001) after one cycle. Copper depletion was most efficient in TNBC where Cp levels dropped from 23.5 to 13 after one cycle. TM was well tolerated with grade 3/4 toxicities including: reversible neutropenia (2.3%), febrile neutropenia (0.04%), fatigue (0.2%). Five-year analysis showed a decrease in EPC’s (p = 0.004) and LOXL-2 (p < 0.001). At a median follow-up of 6.9 years, the EFS for 75 pts is 75.6%. PFS for 36 pts with TNBC is 79.2%. EFS for stage 2/3 TNBC is 90% and for stage IV TNBC is 66.7%. Conclusions: TM is safe, well tolerated and appears to affect multiple components of the TME creating an inhospitable environment for tumor progression especially in high risk patients such as TNBC. Randomized trials are warranted, especially in patients at high risk for relapse. Clinical trial information: UL1TR000457.

Mitochondrial copper depletion suppresses triple-negative breast cancer in mice

“… 52 – 54 The most successful case so far is seen in a Phase II clinical trial with TM as a chemo-preventive method in prolonging the recurrence-free window of patients with no trace of tumor by the time of the treatment. 55 – 57 Moreover, both molecules deplete copper systemically, and serious concerns have been raised that it may result in overall copper deficiency and induce hematological disorder and neurotoxicity. Functioning differently than these conventional copper chelators, CDN induced mitochondrial dysfunction and altered the metabolism of TNBC cells.…”

Copper as the Target for Anticancer Nanomedicine

“…TM is one of the predominant medicines to treat copper accumulation. [48,[67][68][69][70][71][72][73][74] A small phase II clinical trial showed that the event-free survival for 75 advanced breast cancer patients with TM-treatment was 75.6% at a median followup of 6.9 years (ClinicalTrials.gov Identifier: NCT00195091). [66] Given with meals, TM complexes copper contained in food proteins and thereby prevents the absorption of copper.…”

“…It acts by forming a tripartite TM-copper-protein complex, from which the copper is unavailable for cellular uptake. [74] D-pen is also an effective copper chelator and has been shown in in vivo studies to remove excess copper as effective as TM. Given between meals, TM is absorbed into the blood, and forms complexes with serum copper and albumin, reducing the bioavailable copper.…”

“…Given between meals, TM is absorbed into the blood, and forms complexes with serum copper and albumin, reducing the bioavailable copper. A handful of preclinical and clinical studies ( Table ) have demonstrated TM as a promising anticancer agent . A small phase II clinical trial showed that the event‐free survival for 75 advanced breast cancer patients with TM‐treatment was 75.6% at a median follow‐up of 6.9 years (ClinicalTrials.gov Identifier: NCT00195091) …”

Responsively Aggregatable Sub-6 nm Nanochelators Induce Simultaneous Antiangiogenesis and Vascular Obstruction for Enhanced Tumor Vasculature Targeted Therapy

“…Copper is essential in the expression, activation, and secretion of multiple angiogenic factors . Therefore, depleting the copper level to a therapeutic window, wherein the normal physiologic functions with a low copper requirement can be maintained while the angiogenic process with a high copper consumption can be delayed or inhibited, has been suggested as a promising antiangiogenic strategy and gained great success in clinical trials. , To accomplish copper depletion in the complex physiological condition, the selectivity of Imi-OSi nanochelators for capturing copper ions was studied in the presence of various biologically relevant metal ions (6 ppm) in 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) buffer at pH 7.0. Figure a shows the high selectivity of Imi-OSi nanochelators toward copper over other metal ions despite a minor interference from iron.…”