tbuckley/cabot-search huggingface dataset:
Abstract 5436: Targeting oncoproteins via disruption of proteostasis: Identification of oncoprotein destabilizing agents using luciferase tagged oncoproteins
Authors: Richard E. Middleton, Greg Olsen, Russell McSweeney, Gang Lu, Wenhua Gao, Justin Roberts, Michael R. McKeown, Mark A. Bittinger, Kwok-Kin Wong, James E. Bradner, William G. Kaelin
Journal: Cancer Research (2015)

Abstract Since many oncoproteins are considered undruggable targets, we have developed and validated a new screening strategy to identify small molecules that inhibit oncoprotein activity by causing their degradation. Recently, the mechanism of action for the class of drugs known as immunomodulators (IMiDs; e.g. thalidomide, lenalidomide and pomalidomide) has uncovered a novel oncogene targeting strategy. IMiDs commandeer an E3 ligase complex that contains the E3 recognition subunit cereblon and divert its activity toward two transcription factors IKZF1 and IKZF3, which play critical roles in hematopoietic cells. This mechanism explains the efficacy of IMiDs in multiple myeloma and may translate into a general approach to target traditionally undruggable oncoproteins. We generated cell lines stably expressing IKZF1as a firefly luciferase fusion protein with coexpression of Renilla luciferase. A pilot HTS campaign was run to uncover novel drugs that can mimic the effects of IMiDs. A cell line expressing the MYC-firefly fusion protein was used for counter-screening. We used pomalidomide as our positive control and it reduced firefly luciferase signal ≈75% with no change in the renilla luciferase signals. This control resulted in a Z prime value typically &amp;gt;0.5. The pilot screen of 3,850 compounds resulted in 39 “hits” that reduced firefly luciferase &amp;gt;35%. More importantly, both thalidomide and lenalidomide were found to be active in the screen. Confirmation testing revealed that 75% of “hits” repeated, but also had activity in the MYC-firefly cell line. Actives were tested in western blots for their ability to decrease fusion protein abundance. Many active compounds did not reduce protein levels in western blots and represent nonspecific hits (e.g. luciferase inhibitor). In conclusion, we present a screening paradigm with the potential to uncover novel proteostasis disruptors by expressing luciferase tagged oncoproteins. Citation Format: Richard E. Middleton, Greg Olsen, Russell McSweeney, Gang Lu, Wenhua Gao, Justin Roberts, Michael R. McKeown, Mark A. Bittinger, Kwok-Kin Wong, James E. Bradner, William G. Kaelin. Targeting oncoproteins via disruption of proteostasis: Identification of oncoprotein destabilizing agents using luciferase tagged oncoproteins. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5436. doi:10.1158/1538-7445.AM2015-5436
Is there a relationship between glucocorticoid (GC) dose and performance on functional outcome measures?
Authors: J. S. Scheetz, C. A. Brown, N. V. Paddison, G. S. Morris, K. Shin
Journal: Journal of Clinical Oncology (2010)

6542 Background: Functional tests are often used to assess the severity of weakness and fatigue experienced by patients undergoing GC therapy. The relationship between GC dosage and performance on these tests is unknown. We aim to determine the strength of association between these sets of variables. Methods: We retrospectively reviewed the medical records of 34 sub-acute stem cell transplant (allogeneic) patients treated with GCs to determine their cumulative GC dosage between transplant and physical therapy (PT) initial evaluation, number of days of GC exposure and average daily dosage. Outcomes on 3 functional measures were collected at PT initial evaluation, including the 6 min walk test (ft), 50 ft walk time (sec) and repeated sit to stand (sec, S-T-S). The institutional review board approved this study. Central tendency data were calculated. The strength of correlation between GC dosage and scores on three functional outcome measures was determined using regression analysis. Results: These patients (20 males; 50.5 ± 12.87 yrs old) received a median cumulative GC dose of 2,106 mg (range 195-4486 mg) over a median duration of GC exposure of 22 days (range 5-60 days) for a median daily GC exposure of 82.1 mg/day (range 24.6-140.9). Modest correlations existed between 1) cumulative dose and 50 ft walk time (r = 0.3677) and repeated S-T-S time (r = 0.3154), 2) duration and 50 ft walk time (r = 0.3781) and 3) average daily dose and repeated S-T-S time (r = 0.3269). Other correlations were poor, ranging from r = -0.1534 to r = 0.2010. Conclusions: GC dosage has minimal to no relationship with outcomes on functional tests intended to measure strength and endurance. Other assessments such as isolated strength testing of key muscles may be necessary to more accurately reflect the severity of muscle weakness and concomitant disability associated with GC treatment. No significant financial relationships to disclose.
Phase I trial of oral cyclophosphamide in combination with celecoxib in patients with advanced malignancies
Authors: P. Twardowski, W. Chow, M. Koczywas, L. Leong, D. Lim, K. Margolin, R. Morgan, C. Ruel, S. Shibata, T. Synold, J. Doroshow
Journal: Journal of Clinical Oncology (2005)

3196 Background: Preclinical studies demonstrate anti-angiogenic activity with low doses of cyclophosphamide. Selective cyclooxygenase-2 inhibitors are also potent inhibitors of angiogenesis. The objective of this trial was to describe the toxicities of the combination of low dose cyclophosphamide with escalating doses of celecoxib in patients with advanced malignancies. Methods: Patients were treated with a fixed dose of oral cyclophosphamide at 50 mg daily. There were four dose levels of celecoxib:100mg/ 200mg/ 300mg/ 400mg twice daily. Four weeks of therapy constituted one cycle. The celecoxib dose level of 400 mg twice daily was expanded to allow the initiation of a companion biological correlative study to assess changes in the levels of circulating endothelial cells and endothelial cell precursors in patients during therapy. Results: Fifty five patients (34 F; 21 M) were entered. Median age was 56 (28–79). The most common tumor types included: ovary (10), lung (6), breast (5), adenocarcinoma of unknown primary (4), colon (3), rectal (2), prostate (2), cervical cancer (1). The majority of patients were heavily pre-treated with standard chemotherapy regimens. Drug-related grade 3 and 4 toxicities included neutropenia (3), anemia (3), fatigue (3), nausea (3), and thrombosis (2). No patients died from adverse effects related to drug toxicity. One patient with metastatic cervical cancer had unconfirmed partial response. Sixteen patients had stable disease for at least 8 weeks. The longest duration on therapy was 496 days in a patient with primary peritoneal carcinoma. Conclusions: The combination of oral cyclophosphamide at 50 mg daily and celecoxib 400 mg twice daily is well tolerated. There was less myelosuppression and mucositis as compared to our parallel study with etoposide and celecoxib. No excessive thrombotic, hemorrhagic or cardiovascular complications related to celecoxib were observed. Further study of this regimen is warranted, but potential clinical benefit is unlikely to be reflected by traditional tumor response criteria. Supported by NCI CA62505 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer
Abstract 14653: Patients with Growth Hormone Deficiency Have Global Atrial Dysfunction, Both Intrinsic, and Ventricular Dysfunction Related
Authors: Sorina Mihaila, Raluca Mincu, Roxana Cristina Rimbas, Mircea Cinteza, Corin Badiu, Dragos Vinereanu
Journal: Circulation (2012)

Purpose:  Growth hormone deficiency in adults (GHD) is associated with increased cardiovascular events and we showed that GHD patients have subclinical bi-ventricular dysfunction. Our purpose was to further evaluate left atrial (LA) function and relation to LV dysfunction in these patients, by comparison with normal (N) individuals with similar cardiovascular risk profile.   Methods:  31 GHD patients (46±15yrs, 20 men) were compared to 31 age- and sex- matched N, using conventional and 2D strain echo. LA function was evaluated from 4C, 2C, and 3C views, using the P-wave onset as the reference point. We measured LA volumes at mitral valve closure and opening (MVCvol, MVOvol), at P-wave onset (Pvol), and global LA strain and strain rate. Active LA function was assessed by active EF (EFa=Pvol-MVCvol/Pvol), negative global atrial strain (GAS-) and late diastolic strain rate (GSRL); passive function from passive EF (EFp=MVOvol-Pvol/MVOvol), first/second positive global strain (GAS1+, GAS2+), and early negative diastolic global strain rate (GSRE); reservoir function from total atrial strain (TAS=GAS- plus GAS2+) and positive global SR at the begining of LV systole (GASR+); we also measured LA expansion index (EIx=MVOvol-MVCvol/MVCvol). Global LV systolic, early and late diastolic strain rate (GLSRs, GLSRe,GLSRl) were assessed from similar LV apical views.   Results:  GHD patients had similar MVO- and P-vol, but increased MVCvol. They had significantly decreased LA active function (EFa, GAS- and GSRL). Passive LA function (GAS2+), and reservoir function (TAS, GSRL) were significantly decreased, with lower EIx. Active LA function (GAS-) correlated with LV GLSRl (r=410, p=0.03), passive and reservoir LA function (GAS1+, GAS2+, TAS) with GLSRe (r=0.58, r=0.65, respectivelly r=0.58, p   Conclusions:  GHD patients have global LA dysfunction with impairment of both intrinsic contraction, and passive relaxation induced by LV diastolic dysfunction.
Results of concurrent chemoradiotherapy (CRT) with low dose weekly gemcitabine (G) in stage III non-small cell lung cancer (NSCLC)
Authors: U. Abacioglu, P. F. Yumuk, H. Caglar, M. Sengoz, N. S. Turhal
Journal: Journal of Clinical Oncology (2004)

7318 Background: Combined CRT is the treatment of choice for stage III NSCLC. G is a novel deoxycitidine analogue that has been proven to be a potent radiosensitizer. To demonstrate the tolerability and efficacy of low dose G given weekly as a radiosensitizer in stage III NSCLC, 22 patients were treated with concurrent CRT. Patients and Methods: Patients with KPS ≥70, adequate bone marrow reserve, without prior RT and surgery were included. Eighteen patients had received prior induction CT. G (75 mg/m2/week) was infused over 1 hour for 6 weeks. Two hours later thoracic RT was given over 6 weeks with 1.8 Gy/day (total dose 61.2 Gy). Pulmonary toxicity was evaluated with CT scans 6 weeks after RT and treated accordingly. Results: Median follow-up was 15 months (range, 2–40). Half of the patients had stage IIIA disease. Median age was 60 years (range, 48–75), 68% were male and median KPS was 90. Conformal 3D RT planning was used in 64% of patients. G was given for a median of 5.5 weeks (range, 1–9). Twelve patients (54.6%) received all planned CT. G was stopped because of intolerance (grade 2 nausea/vomiting, neutropenia and grade 3 esophagitis) in 6 and death in 2 patients. Eight patients (36.4%) had radiation pneumonitis, 7 were grade 1/2 and 1 was grade 5. One patient (4.5%) had clinical CR, 81.8% had PR while 9.1% had SD. Sixteen patients died, 6 with progression of primary, 8 due to metastatic disease, 1 with pulmonary toxicity and another one with cerebrovascular accident. Conclusion: Gemcitabine used as radiosensitizer during the primary RT of stage III NSCLC patients is a promising agent revealing increased local control with tolerable toxicity profile in patients with good performance status. No significant financial relationships to disclose.
Phase II trial of adjuvant hyperthermic intraperitoneal chemotherapy with three drugs for the prophylactic treatment of carcinomatosis after resection of advanced gastric cancer
Authors: S. Murata, H. Naito, H. Yamamoto, E. Mekata, T. Shimizu, H. Shiomi, S. Naka, H. Abe, Y. Kurumi, T. Tani
Journal: Journal of Clinical Oncology (2009)

e15588 Background: This prospective study was performed to assess the efficacy and safety of hyperthermic intraperitoneal chemotherapy (HIPEC) with three drugs in patients with curative resection of T3 or T4 advanced gastric cancer. Methods: Patients with curative resection of clinically T3 or T4 advanced gastric cancer were required to be under 75 years of age and to have adequate organ function. After the curative resection of gastric cancer with D2 lymph node dissection and the reconstruction of the alimentary tract, HIPEC was carried out for 30 minutes with 50mg of CDDP, 10mg of MMC, and 1000mg of 5-FU in 5 L saline maintained at 42–43°C. Patients were given an adjuvant S-1 treatment after surgery. Primary endpoint of this study was overall survival. Results: A total of 29 patients were eligible. Pathologically, 8 patients had sub-serosal invasion (pT2(ss)), 18 patients had serosal invasion (pT3), and 3 patients had adjacent organ invasion (pT4). These patients included pT2(ss)pN0 (n=2), pT2(ss)pN1 (n=6), pT3pN0 (n=4), pT3pN1 (n=9), pT3pN2 (n=5), pT4pN0 (n=1), and pT4pN1 (n=2). Median follow-up period was 44 months (10–72 months). Overall 5- year survival rate in all eligible patients was 89.5%. Overall 5-year survival rate in patients with pT2(ss), pT3, or pT4 was 100%, 82.4%, or 100%, respectively. Three patients with pT3 had recurrence of pleural dissemination (n=1), lymph node metastases (n=1), or pulmonary metastases and peritoneal dissemination (n=1). A total of 7 patients had postoperative complications such as continuous pancreatic juice secretion (13.8%), abdominal abscess (10.3%), leakage of the anastomosis (3.4%), and pulmonary insufficiency (10.3%). Conclusions: The present study suggests that HIPEC with three drugs after curative resection of advanced gastric primary cancer is associated with improved overall survival with an acceptable morbidity. No significant financial relationships to disclose.
Clinical results of preoperative chemoradiotherapy using short-term schedule (25 Gy) and long-term schedule (45-50.4 Gy) for lower rectal cancer.
Authors: H. Yanagi, N. Kamikonya, C. Yasui, T. Aihara, S. Ikuta, H. Iida, H. Tsubamoto, S. Matsumoto, N. Tomita, N. Yamanaka
Journal: Journal of Clinical Oncology (2010)

e14035 Background: It has been reported that preoperative radiotherapy (PRT) for lower rectal cancer (LRC) result in decreased local recurrence. Recently long-term PRT (45–55 Gy) is more effective in circumferential infiltration than short-term PRT (25 Gy) by pathological analysis. We introduced short-term PRT with chemotherapy for T3-4 LRC in 1996, and found that R0/R1 resectability could not be achieved in few T4 cases. To improve resectability, we have applied short-term PRT for resectable LRC, and long-term PRT for locally advanced LRC since 2001. We aim to document resectability, local control rate, and adverse effects in LRC patients (pts.) treated by PRT with two different schedules. Methods: We reviewed 220 pts. with lower rectal adenocarcinoma treated by PRT at our institution from 1996 to 2009. They were 89 pts. with T3-T4 tumor treated by short-term PRT (4 Gy × 5) with uracil/tegafur (UFT) and oral leucovorin in 1996–2001 (Group A), and 131 pts. with T3-4 tumor, treated by short-term PRT (5 Gy × 5) with S-1 (117 pts.), or with T4 tumor treated by long-term PRT (45–50.4 Gy) with S-1 plus weekly irinotecan (14 pts., male) in 2001–2009 (Group B). Rectal resection was performed within 10 days after short-term PRT, and 6 week after long-term PRT. In this series, all pts. were consecutive and treated by same surgical team in single institution for these 13 years. Results: Response rate was 72% in Group A and 75% in Group B. Resectability (R0, R1) were found 94% in Group A, and 96% in Group B. Cumulative local control rate at 3 years were 91% in Group A, and 94% in Group B (p = 0.29). Anus preserving operation was performed in 81 pts. (91%) of Group A and 123 pts. (94%) of Group B. The preserving rate of bladder cyst was 99% in Group A, and 100% in group B. Adverse effect found in 64% in pts. treated with long-term PRT, 33% in pts. with short-term PRT. Conclusions: There have been already achieved satisfying oncologic results in lower rectal cancer patients treated by short-term preoperative radiotherapy. Long-term preoperative radiotherapy with intensive chemotherapy is, however, necessary for T4 tumor of male, invading anterior urogenital organ to improve resectability and preserve pelvic function. No significant financial relationships to disclose.
Isolation perfusion for malignant melanoma of the extremity: a review.
Authors: R Cumberlin, E De Moss, M Lassus, M Friedman
Journal: Journal of Clinical Oncology (1985)

The role of perfusion, normothermic and hyperthermic, in the curative treatment of melanoma remains controversial. Survival appears to be somewhat improved over that of surgery alone in all stages, especially with hyperthermic perfusion, but all comparisons have been retrospective and uncontrolled. In addition to the usual problems with historical controls, melanoma presents its own special problems because of its unpredictable natural history in any given individual and the multiplicity of factors known to affect prognosis. It is unfortunate that hundreds of patients have been treated in uncontrolled studies. Randomized trials continue to be necessary to define this role and even then careful attention will have to be paid to the distribution of known prognostic factors in each group to insure a comparable cohort of patients. The response of melanoma to perfusion is clearly significant, however, and the response rate seems to be improved with hyperthermic perfusion. Hyperthermic perfusion appears to be a useful palliative treatment for locally advanced melanoma of the extremity, especially for which the alternative surgical therapy would be amputation.
Capecitabine (X) in elderly patients (pts) with hormone-refractory metastatic breast cancer (MBC)
Authors: C. G. Messina, F. Longo, M. Di Seri, M. Restuccia, A. Zivi, E. Proietti, M. Russillo, L. Cerbone, V. Bianco, I. Speranza, G. M. L. Basile, L. De Filippis
Journal: Journal of Clinical Oncology (2007)

1080 Background: X has demonstrated consistently high single-agent activity and good tolerability in pretreated and chemonaive MBC, and extends survival when added to docetaxel. High activity, minimal myelosuppression and no alopecia make X interesting in elderly pts with hormone-refractory disease. Methods: Between Feb 2004 and Oct 2006, 36 elderly (&gt;65 years) MBC pts previously treated with adjuvant therapy and at least one previous hormonal therapy for advanced disease received X 1,000 mg/m 2 twice daily, days 1–14 every 3 weeks. Study objectives were to assess efficacy, safety, and impact on quality of life (QoL), assessed by Clinical Benefit Response (CBR) every third cycle. Results: Median age was 70 years (range 68–73), median ECOG PS was 1 (range 0–2). All pts had visceral metastasis and 19 (53%) had ≥2 metastatic sites. A total of 284 cycles were administered (median 6 cycles per pt). After 3 cycles, 10 pts (28%) showed a partial response, 16 (44%) had stable disease (SD), and 2 (6%) had a minor response, resulting in a disease control rate of 78%. Biochemical response (CEA and/or CA 15.3 reduction) was observed in 20 (56%) pts. SD was maintained in 22 pts (61%) after 6 cycles, 10 pts (28%) after 9 cycles and 2 pts (6%) after 12 cycles. Treatment was well tolerated, the most common grade 3 events being mucositis (6%) and hand-foot syndrome (6%). There were no grade 3/4 hematologic toxicities. All adverse events were easily managed with dose adjustments and supportive therapies as required. As a result, all pts (100%) complied with appreciable benefits in terms of QoL (positive CBR in 56% of pts). Conclusions: These preliminary data indicate that this X dose is active and well tolerated in elderly pts with hormone-refractory MBC. This regimen also warrants study as first-line treatment in pts with less aggressive MBC who might not be suitable for combination therapy. No significant financial relationships to disclose.
French, multicentric, prospective study of dynamic contrast-enhanced ultrasound (DCE-US) for the evaluation of antiangiogenic treatments in 400 patients.
Authors: N. Lassau, J. Lacroix, S. Taieb, R. Aziza, V. Vilgrain, M. Cuinet, A. Sarran, C. Labbe, A. Jean-Pierre, S. Koscielny
Journal: Journal of Clinical Oncology (2010)

3036 Background: A prospective evaluation of dynamic contrast-enhanced ultrasound (DCE-US) with quantification to evaluate antiangiogenic treatments was launched in 2007 in 20 French comprehensive anticancer centers with 65 radiologists, supported by the French National Cancer Institute. The objectives were to diffuse the standardized method, a cost evaluation and the identification of perfusion parameters predicting tumor response to different anti-angiogenic treatments. Methods: All patients had an examination just before the start of the antiangiogenic treatment (D-1) and at D7, D14, D30 and D60. Each examination included a bolus injection of stabilized sulphur hexafluoride microbubble-based contrast agent (SonoVue, Bracco) and registration of raw linear data over 3 minutes with an Aplio(Toshiba). Raw data were analyzed with a mathematical model (patent PCT/IB2006/003742) to evaluate 7 parameters characterizing the tumor perfusion curve. The quantification of DCE-US raw data was done blinded to clinical data. Response to treatment was evaluated every 2 months with RECIST criteria. Complete or partial responses and stabilization were classified as successes and progressions as treatment failures. Patients were not considered evaluable if treatment was stopped before the first CT evaluation at 2 months or when an increase in drug dose was followed by a success. In order to have sufficient follow-up data, the statistical analysis must be performed more than 6 months after the inclusion of the last patient. Results: Since October 2007, 480 patients have been included (mainly with renal cell carcinomas [127] and hepato-cellular carcinoma [85]). More than 1,600 DCE-US examinations have been performed. Preliminary results (Dec 2009) concerning 400 patients followed up for more than 6 months show that 5 parameters exhibited a significant difference (p<0.009) in their variation between D-1 and D30 according to the response at 6 months. Conclusions: Our preliminary results confirm the usefulness of this tool for monitoring anti-angiogenic treatments. Continuing accrual in this ongoing prospective multicentric study will allow us to present a complete analysis of more than 400 patients followed up for more than 6 months. No significant financial relationships to disclose.