Introduction FASN inhibition is a novel approach to cancer treatment involving selective disruption of palmitate biosynthesis that, in tumor cells, leads to apoptosis. TVB-2640 is an oral, first-in-class, small molecule reversible inhibitor of FASN that demonstrates in vivo antitumor effects. We previously reported the results of dose escalation and now present evidence of preliminary activity in breast cancer patients treated in the dose expansion cohort. Methods This ongoing international, multicenter Phase I trial enrolls patients (pts) with advanced solid tumors with adequate organ function. TVB-2640 is given orally once daily at the MTD (100 mg/m2) as monotherapy (mono) or in combination (combo) with weekly IV paclitaxel (80 mg/m2). Results The most common AE's observed [mono, N=53; combo, N=47] were: alopecia (57%), palmar-plantar erythrodysesthesia (PPE) (36%), dry eye (13%) and increased lacrimation (11%). Gr. 3 toxicities include corneal edema (3%) and PPE (10%). Other toxicities were ≤ Gr. 2 and only minor GI symptoms occurred. All toxicities were reversible on dose interruption and no enhancement of common paclitaxel toxicity was observed when given with TVB-2640. Rare cases of pneumonitis in combination have been observed but the contribution of TVB-2640 to this effect is uncertain. 14 breast cancer patients were enrolled and treated in combination with weekly paclitaxel while 3 breast patients were given monotherapy (during the dose escalation phase). Among patients treated in combination, three (3) confirmed RECIST partial responses (cPR) were seen and multiple cases of prolonged stable disease (SD) (≥16 wks) despite heavy pre-treatment and taxane resistance in all but 2 cases. One ER+, PR+, Her2+ patient achieved a cPR and was on study for 26 weeks. One ER-/PR-/Her2+ patient whose previous best response to paclitaxel treatment was SD for 24 weeks, reached a cPR at week 12, discontinued paclitaxel at week 21 and remains on monotherapy TVB-2640 with a sustained cPR at week 29. The third responder with cPR is an ER+, PR+, HER2- patient whose previous taxane treatment lasted 15 weeks (response unknown) and she remains on study at week 24. Of the remaining 11 patients, 10 achieved SD > 12 weeks and 8 of the 10 maintained that response for 16-45 weeks. The ongoing SD patient at week 45, discontinued paclitaxel at week 35 and remains on monotherapy TVB-2640. Summary TVB-2640 demonstrated multiple cPRs and prolonged SD when combined with weekly paclitaxel in 93% of patients treated. Further exploration of response in patients recently progressed on a taxane (progression within the prior 6 months) and safety with TVB-2640 in combination with docetaxel is being explored. Citation Format: Brenner AJ, Falchook G, Patel M, Infante JR, Arkenau H-T, Dean EM, Borazanci E, Lopez JS, Moore K, Schmid P, Frankel AE, Jones S, McCulloch W, Kemble G, Grimmer K, Burris H. Heavily pre-treated breast cancer patients show promising responses in the first in human study of the first-In-class fatty acid synthase (FASN) inhibitor, TVB-2640 in combination with paclitaxel [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-11-09.
Introduction: Obesity is associated with a worse prognosis in breast cancer, including the less aggressive ER+ luminal A subtype, but the mechanisms by which it promotes disease progression are unclear, making treatment difficult. Obese breast cancer patients have a higher risk of a more aggressive disease compared to lean patients, which is associated with treatment resistance and metastasis. The mechanisms promoting obesity-driven metastasis are not understood, but several studies have indicated that obesity is associated with a “stem-like” phenotype. A “reprogramming” occurs, transforming stationary, epithelial cells to motile, malignant cells that exhibit a more aggressive phenotype than their stromal counterparts. Our data suggest that in vitro exposure of luminal A breast cancer cells to obese conditions may induce an epithelial to mesenchymal transition (EMT), which is characterized by a more stem-like phenotype, resistance to treatment (chemo, hormone and radiation), as well as greater metastatic potential. This has let us to hypothesize that one critical mechanism by which obesity promotes a more aggressive disease is through inducing an EMT reprogramming, resulting in a more stem-like phenotype. Methods and Results: Both in vitro and translational approaches will be done to determine if obesity induces epigenetic reprograming associated with a more stem-like phenotype. MCF-7 ER+ breast cancer cells exposed to 2% sera from obese (BMI ≥ 30) postmenopausal women demonstrated a significant increase in expression of both SNAIL1 and TWIST transcription factors (9-fold and 4-fold, respectively) which are implicated in EMT and potentially stem-cell programming, compared to those exposed to sera from lean women. Current studies are underway to determine if this is observed in other ER+ luminal A cell lines, including T47D, and whether induced changes in these transcription factors results in changes in signaling pathways associated with EMT, including TGFβ, which can activate the PI3K–AKT, ERK MAPK, p38 MAPK and JNK pathways and WNT signaling, which promotes EMT by stabilizing β-catenin. Additionally, the luminal A cell lines will be assessed for changes in other factors known to modulate breast cancer cell programming, including KLF4, OCT4, SOX2, and NANOG. Conclusions: Our earlier studies have demonstrated that obesity promotes a more aggressive disease even in luminal A disease. The mechanisms for this remain unclear. Our exciting preliminary findings suggest that obesity might induce a reprogramming of the luminal A well-differentiated cell to a more stem-like phenotype. Our results will lay an important foundation for understanding how obesity modulates breast cancer disease progression, whether this programming may provide therapeutic target to improve response and overall survival in the obese patient. Citation Format: Hayden A, Quach D, Galvan G, Patodia R, Brenner A, deGraffenried L. Obesity-induced EMT in luminal A breast cancer cells [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-04-03.
Background: Studies have shown that obesity is associated with a worse breast cancer prognosis. Besides the effect of different stages of diagnosis and co-morbidities, recent data from our published in vitro and retrospective studies suggests that this phenomenon may occur because the obese state promotes a more aggressive cancer phenotype through the cyclooxygenase (COX-2) pathway and its production of prostaglandin E2 (PGE2). The metabolization of omega-3 fatty acids decreases the production of PGE2, and have been shown to have potential benefit to cancer patients by decreasing inflammation-related signaling. Our previous clinical trial showed mixed results in the effect of omega-3 PUFA supplements on PGE2 production in post-menopausal obese women. This led us to the hypothesis that the ratio of omega-3 to omega-6 PUFAs have differential effects on cell types within the tumor microenvironment, impacting cancer cell phenotype. Approach: In vitro experiments, including wound-healing assays to determine motility, and clonogenic assays to determine overall survival, were performed to determine if exposure to higher ratios of omega-6 to omega-3 fatty acids lead to a more aggressive cancer phenotype. MCF-7 breast cancer cells were treated with the following fatty acid ratios of omega-6 (arachidonic acid (AA)) to omega-3 (eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)): 46:1, 20:1, 10:1, and 1.3:1. The wound-healing assays showed greater motility with higher ratios of omega-6 to omega-3 fatty acids conditions and the clonogenic assays showed greater survival with the higher ratios. Conclusion: These data indicate that lowering ratios of omega-6 to omega-3 fatty acids may lessen the aggressiveness of breast cancer cells and be beneficial to some patients. Studies are on-going to investigate the impact of PUFA ratios on cancer cell phenotype directly, including proliferation and invasion, as well as the indirect effects from modulation of the other cells within the tumor microenvironment, including the macrophages and adipocytes. Citation Format: Winikka L, Quach D, Harlow B, Brenner A, Munoz N, Tiziani S, deGraffenried L. The ratio of omega-3 to omega-6 PUFAs impact cancer cell phenotype in the tumor microenvironment [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-03-12.
Background: The incidence of CNS metastatic disease in breast cancer patients (pts) seems to have increased in recent years with the improvement of systemic therapy. However, treatment options for CNS metastases have remained limited due to the inability of most agents to cross the BBB. ANG1005 is a novel peptide drug-conjugate, consisting of 3 paclitaxel molecules covalently linked to Angiopep-2, a peptide designed to utilize the LRP-1 transport system to cross the BBB/BCB and to penetrate malignant cells. Methods: We conducted an open label phase II clinical study to test its activity in metastatic breast cancer (BC) pts with recurrent brain metastasis (BM), including BCBM pts with newly diagnosed leptomeningeal carcinomatosis (LC). Adult pts with measurable, recurrent BM from breast cancer, with or without LC (n=72 safety population; n=58 efficacy population) were enrolled in the study. ANG1005 was administered IV at 600 mg/m2 q3w. HER2+ patients were allowed to continue trastuzumab +/- pertuzumab. Intracranial (IC) response was assessed by Gd-MRI using CNS RECIST 1.1 and extracranial response (EC) was evaluated per RECIST 1.1. Results: Median age was 47.5 (26-76) years. Safety was similar to that of paclitaxel with myelosuppression as the predominant toxicity (WBC: 83%, RBC: 71%, PLT: 69%). Pts received a median of 6 (1-29) prior therapies for BC, including 84% with taxanes. As prior therapy for BM, 87% pts had cranial surgery and/or radiation and 19% pts received systemic therapies. Intracranial tumor response is presented for all pts as well as the various patient subsets as shown below: Table 1: Intracranial Response by Breast Cancer SubsetOutcome by CNS RECISTAllHER2+HER2-TNBCLCSample size, n5828301223PR (best response), n (%)8 (14%)4 (14%)4 (13%)2 (17%)5 (22%)Confirmed PR, n (%)3 (5%)2 (7%)1 (3%)02 (9%)SD, n (%)33 (57%)19 (68%)14 (47%)5 (42%)12 (52%))PD, n (%)17 (29%)5 (18%)12 (40%)5 (42%)6 (26%)Clinical benefit (SD+PR), %71%82%60%59%74%Abbreviations: TNBC, triple-negative breast cancer, a sub-group of HER2-; LC, leptomeningeal carcinomatosis Table 1 definitions: data based on evaluable pts with clinical or radiological evaluation ≥ 4 weeks from C1D1; LC pts included 15 HER2+ and 8 HER2-; best response is the best response recorded from the start of the study treatment until the disease progression; confirmed PR requires a ≥28-day confirmation of response. Extracranial tumor responses of 1 (3%) CR, 2 (7%) PRs and 24 (80%) SDs were seen in 30 evaluable pts, including after prior taxanes (93%). The 6 month OS in all pts was 50.2% (95% CI: 37.4, 61.6). In general, CNS clinical symptoms post-ANG1005 were improved, including in LC pts. Conclusions: ANG1005 is active against previously treated BC metastasis both within and outside the CNS. A randomized study is planned. Updated efficacy and safety data will be presented at the meeting. Citation Format: Ibrahim NK, Tang S-C, Brenner AJ, Kesari S, Piccioni DE, Anders CK, Carillo JA, Chalasani P, Kabos P, Puhalla S, Garcia AA, Tkaczuk KH, Ahluwalia MS, Lakhani NJ, Kumthekar P. A phase II, open-label, multi-center study of ANG1005, a novel brain-penetrant peptide-drug conjugate, in breast cancer patients with recurrent CNS metastases [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-12-01.
Epidemiological studies indicate that obesity increases the risk of breast cancer by approximately 50% in postmenopausal women. This population most commonly develops estrogen receptor (ER) alpha positive breast cancer, suggesting that elevated estrogen synthesis by the adipose tissue and local mammary epithelia is the primary mediator of breast tumorigenesis in obese postmenopausal women. However, the specific mechanisms by which obesity promotes the development of postmenopausal breast cancer remain unclear. In vitro and animal studies have indicated that obesity-associated growth factor and cytokine signaling also play a role in breast tumorigenesis. Specifically, obesity is accompanied by elevated levels of insulin, insulin-like growth factor 1 (IGF-1), and leptin, and these all have significant tumorigenic effects in the breast. In the current study, we utilize an in vitro model of obesity to examine the effects of elevated circulating hormones and growth factors on breast cancer cells. C57BL/6 mice were randomized at six weeks of age to either a 60% fat diet to induce obesity or a 10% fat diet to produce a lean comparison and maintained on these diets for 12 weeks prior to sacrifice. Sera was obtained from the mice at the time of euthanasia and used to treat ER alpha positive MCF-7 breast cancer cells at a concentration of 2% in serum-free media. Preliminary data indicates that sera from the obese mice induces 31% greater proliferation of MCF-7 cells in comparison to sera from lean animals (p=0.0025). This proliferation is mediated primarily via a phosphoinositide 3-kinase (PI3K) pathway, as evidenced by the ability of LY294002, a PI3K inhibitor, to neutralize the proliferative effect of the obese sera. The addition of LY294002 to MCF-7 cells treated with 2% obese sera decreased proliferation by 43% (p=0.0083). Intriguingly, tamoxifen did not significantly affect proliferation in the cells treated with obese sera (p=0.2425), suggesting that obesity may induce tamoxifen resistance. Consequently, we hypothesize that obesity promotes breast cancer progression and tamoxifen resistance via cross-talk between growth factor and ER alpha signaling pathways. Further studies will be conducted to examine the pathways through which circulating factors mediate obesity-induced breast cancer progression. These will include measurement of the expression and activation of ER alpha, Akt, Erk1/2, IGF-1 receptor, and other proteins in MCF-7 cells in response to treatment with sera from obese and lean mice. By improving our understanding of the mechanisms linking obesity and post-menopausal breast cancer risk, we ultimately hope to develop a rational and effective chemopreventive regimen for this population. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD09-06.
Introduction: Obesity is associated with a worse breast cancer prognosis, with the most prominent effects seen in hormone responsive postmenopausal patients. It has also been linked to elevated levels of inflammation, including greater cyclooxygenase-2 (COX-2) expression and activity in adipose-infiltrating macrophages. The product of this enzyme, the pro-inflammatory eicosanoid prostaglandin E2 (PGE2), stimulates adipose tissue aromatase expression and subsequent estrogen production, which could promote breast cancer progression. Consequently, we hypothesized that non-steroidal anti-inflammatory drug (NSAID) use decreases estrogen receptor (ER) positive breast cancer recurrence in the obese population via inhibition of PGE2-mediated local aromatase expression. Methods: Four-hundred and forty women treated for invasive, ER positive breast cancer at San Antonio area clinics were retrospectively classified according to NSAID use, body mass index category (Normal Weight (NW): 18.5-24.9 kg/m2; Overweight (OW): 25.0-29.9 kg/m2; Obese (OB): ≥30.0 kg/m2), and disease recurrence. To examine the role of obesity-induced local aromatase expression in the link between NSAID use and disease recurrence, we utilized an in vitro model of obesity in which we exposed macrophages to pooled sera samples from NW or OB postmenopausal breast cancer patients. Adipose stromal cells’ (ASC) aromatase expression was measured following exposure to conditioned media (CM) collected from these sera-exposed macrophages. ER activity and in vitro measures of cancer aggression were assessed in MCF-7 and T47D breast cancer cells cultured in CM from sera-exposed macrophage/ASC co-cultures. Results: Within our patient population, which had an average BMI in the obese range, NSAID users had significantly lower recurrence rates (p = 0.05) and their time to disease progression was delayed by almost 28 months in comparison to nonusers. Our in vitro studies demonstrated that growth in OB macrophage CM significantly enhances ASC aromatase expression in comparison to NW (p<0.05), while macrophage treatment with celecoxib during the generation of CM neutralizes the difference between OB and NW. This was correlated with significantly greater macrophage PGE2 production following OB versus NW sera exposure (p<0.05). In addition, CM from macrophage/ASC co-cultures exposed to OB patient sera stimulates more breast cancer cell ER activity, proliferation, and S phase activity, and these differences are eliminated by the addition of an aromatase inhibitor during the generation of CM. We also plan to examine how the co-culture CM impacts breast cancer cell expression of a panel of genes related to cancer aggression. Conclusions: Our results indicate that NSAID use can improve the recurrence rate for hormone-responsive breast cancer patients, particularly those with an elevated BMI. The in vitro model suggests that obesity-related enhancement of PGE2-induced local aromatase expression and estrogen production may be a key mechanism mediating this effect. Further studies designed to examine the clinical benefit of NSAID use in the obese breast cancer patient population are warranted. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-06-01.
Introduction: Obesity is associated with poor breast cancer outcomes in postmenopausal women in response to aromatase inhibitor therapy. Our prior studies have shown an association between reduced recurrence rate and use of cyclooxygenase-2 (COX-2) inhibiting non-steroidal anti-inflammatory drugs (NSAIDs) in obese breast cancer patients. The mechanism proposed was a decrease in prostaglandin E2 (PGE2) and reduced activation of the aromatase promote locally in the breast. Methods: Postmenopausal women of varying body habitus were recruited at the CTRC in San Antonio and underwent randomized assignment to 1 of 3 arms: ASA 81mg daily, 1500mg of docosahexaenoic acid (DHA) and 2500mg eicosapentaenoic acid (EPA) given daily, or combined ASA and DHA/EPA. Sera were collected prior to and following 28 days of exposure, and cytokines including prostaglandin E2 were assessed via enzyme-linked immunosorbant assay (ELISA). Conditioned media was generated by exposing macrophages to patient sera in order to see if the patient sera induced PGE2 concentration in vitro. Results: Thirty of the planned 120 subjects have completed assessment. No toxicity has been noted. In 71% of the patients, serum PGE2 levels decreased, but only 60% demonstrated concurrent decrease in serum PGE2 levels as well as macrophage PGE2 production, while almost all (88%) of the patients whose serum did not demonstrate a decrease in PGE2 levels also demonstrated no decrease in induced levels. Conclusion: NSAIDs appear to effectively decrease circulating levels of PGE2 in most obese women. However, one third of the subjects did not demonstrate concurrent suppression of induced PGE2 from macrophages. These data suggest that circulating levels of PGE2 may not be reflective of local tumor microenvironment levels, and other pro-inflammatory circulating factors may be responsible for regulating local inflammatory responses. Final analysis will be completed and presented at the SABCS meeting. Citation Format: Lengfelder L, Brenner A, Bowers L, Apte S, Galván G, Kist K, deGraffenried L. Phase 0 study evaluating COX2 inhibition on circulating PGE2 levels from obese subjects. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-14-12.
Background: Treatment options for brain metastases are limited to local therapies due to the inability of most anti-cancer agents to cross the blood brain barrier (BBB). ANG1005 is a novel taxane derivative, being developed for targeted treatment of brain metastases. It consists of 3 paclitaxel molecules covalently linked to Angiopep-2 designed to cross the BBB and to penetrate malignant cells, regardless of location, via the low density lipoprotein (LDL) receptor related protein-1 (LRP-1) transport system. Methods: Adult patients with measurable recurrent brain metastases from breast cancer with, or without, leptomeningeal disease are currently being enrolled in this multi-center, open-label study (planned n=56). ANG1005 is administered IV at 600 mg/m2 every three weeks (one cycle) until disease progression, unacceptable toxicity or consent withdrawal. HER2+ patients are allowed to continue HER2 targeted therapies. The primary endpoint is intracranial objective response rate, as assessed by MRI using CNS RECIST 1.1. Secondary endpoints include duration of intracranial response, median progression-free survival, 3/6/12-month progression-free survival rate, overall survival at 6 months, extracranial objective response rate, safety and tolerability. Extracranial response is also assessed by CT using RECIST 1.1. An imaging sub-study, evaluating the use of 18F-FLT-PET in comparison to MRI, is also ongoing in 10 patients with measurable brain metastases from breast cancer, receiving ANG1005 IV at 550 mg/m2. Results: Accrual is ongoing and to date, 48 patients have been treated with a range of 1-18 cycles of ANG1005. Median age is 47 years (range: 26-65). Safety profile is similar to that of paclitaxel with myelosuppression as the predominating toxicity. Based on data from patients evaluated to date for intracranial response, 6/30 (20%) patients had a partial response (PR) and 17/30 (57%) had a stable disease (SD), as best response. A sub-analysis, based on breast cancer sub-type is presented below: Intracranial Response by Breast Cancer SubsetOutcome by CNS RECISTHER2- (n=13)HER2+ (n=17)TNBC (n=6)LMD (n=11)PR, n (%)1 (8%)5 (29%)1 (17%)4 (36%)SD, n (%)6 (46%)10 (59%)2 (33%)5 (45%)PD, n (%)6 (46%)2 (12%)3 (50%)2 (18%)TNBC, triple-negative breast cancer, a sub-group of HER2-; LMD, leptomeningeal disease, including 3 HER2- and 8 HER2+ patients The longest duration on treatment is for 18 cycles, seen in a patient with an intracranial PR that sustained for 10 cycles; the treatment is still ongoing. Extracranial tumor evaluations were completed in 14 patients, all showing disease control including in those previously treated with paclitaxel. One (7%) patient had a PR and 13 (93%) patients had an SD. Conclusions: CNS activity was observed in all subsets of breast cancer, suggesting that ANG1005 is a promising therapy for treatment of brain and leptomeningeal metastases from breast cancer. ANG1005 treatment also resulted in disease control in extracranial lesions, including patients previously treated with paclitaxel. The dose and treatment regimen were well tolerated with a safety profile similar to paclitaxel. Updated efficacy and safety data will be presented at the meeting. Citation Format: Tang S-C, Bates S, Kesari S, Brenner AJ, Anders CK, Garcia A, Ibrahim NK, Tkaczuk KHR, Kumthekar P. A phase II, open-label, multi-center study of ANG1005, a novel brain-penetrant taxane derivative, in breast cancer patients with recurrent CNS metastases. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-17-04.
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