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Despite some notable successes, there are still relatively few agents approved for cancer prevention. Here we review progress thus far in the development of medicines for cancer prevention, and we outline some key concepts that could further enable or accelerate drug development for cancer prevention in the future. These are summarized under six key themes: (i) unmet clinical need, (ii) patient identification, (iii) risk stratification, (iv) pharmacological intervention, (v) clinical trials, and (vi) health care policy. These concepts, if successfully realized, may help to increase the number of medicines available for cancer prevention.Significance:The huge potential public health benefits of preventing cancer, combined with recent advances in the availability of novel early detection technologies and new treatment modalities, has caused us to revisit the opportunities and challenges associated with developing medicines to prevent cancer. Here we review progress in the field of developing medicines to prevent cancer to date, and we present a series of ideas that might help in the development of more medicines to prevent cancer in the future.

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Introduction The compound named 4-[10-(4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)butanamido)decyl]-11-[10-(β, d -glucopyranos-1-yl)-1-oxodecyl]-1,4,8,11-tetraazacyclotetradecane-1,8-diacetic acid is a newly synthesised molecule capable of binding in vivo to albumin to form a bioconjugate. This compound was given the name, GluCAB(glucose-chelator-albumin-binder)-maleimide-1. Radiolabelled GluCAB-maleimide-1 and subsequent bioconjugate is proposed for prospective oncological applications and works on the theoretical dual-targeting principle of tumour localization through the “enhanced permeability and retention (EPR) effect” and glucose metabolism. Methods The precursor, GluCAB-amine-2, and subsequent GluCAB-maleimide-1 was synthesised via sequential regioselective, distal N-functionalisation of a cyclam template with a tether containing a synthetically-derived β-glucoside followed by a second linker to incorporate a maleimide moiety for albumin-binding. GluCAB-amine-2 was radiolabelled with [64Cu]CuCl2 in 0.1 M NH4OAc (pH 3.5, 90 °C, 30 min), purified and converted post-labeling in 0.01 M PBS to [64Cu]Cu-GluCAB-maleimide-1. Serum stability and protein binding studies were completed according to described methods. Healthy BALB/c ice (three groups of n = 5) were injected intravenously with [64Cu]Cu-TETA, [64Cu]Cu-GluCAB-amine-2 or [64Cu]Cu-GluCAB-maleimide-1 and imaged using microPET/CT at 1, 2, 4, 8 and 24 h post-injection. Biodistribution of the compounds were determined ex vivo after 24 h using gamma counting. Results GluCAB-maleimide-1 was synthesised in five consecutive steps with an overall yield of 11%. [64Cu]Cu-GluCAB-amine-2 (97% labelling efficiency) was converted to [64Cu]Cu-GluCAB-maleimide-1 (93% conversion; 90% radiochemical purity). Biodistribution analysis indicated that the control compounds were rapidly and almost completely excreted as compared to [64Cu]Cu-GluCAB-maleimide-1 that exhibited a prolonged biological half-life (6–8 h). Both, [64Cu]Cu-GluCAB-maleimide-1 and -amine-2 were excreted through the hepatobiliary system but a higher hepatic presence of the albumin-bound compound was noted. Conclusions, advances in knowledge and implications for patient care This initial evaluation paves the way for further investigation into the tumour targeting potential of [64Cu]Cu-GluCAB-maleimide-1. An efficient targeted radioligand will allow for further development of a prospective theranostic agent for more personalized patient treatment which potentially improves overall patient prognosis, outcome and health care.

Background: Ataxia telangiectasia and Rad3-related (ATR) protein kinase plays a critical role in the DNA damage response. M1774, a potent, selective, orally administered ATR inhibitor with antitumor activity in preclinical models, was evaluated as monotherapy in Part A1 of the first-in-human open-label, single-arm study (NCT04170153). M1774 was well-tolerated and pharmacodynamic analyses showed that maximum target engagement was reached from the dose of 130 mg QD. The totality of evidence, including quantitative model-based analyses, suggested the recommended dose for expansion (RDE) as 180 mg QD 2 weeks on/1 week off.1 One patient with platinum and PARP inhibitor-resistant BRCAwt ovarian cancer and ATRX mutation on local tumor testing achieved an unconfirmed RECIST v1.1 partial response. Retrospective analyses were conducted to explore the molecular portrait and evolution of the underlying disease of patients treated with M1774. Methods: Archival tumor biopsies, baseline and serial on-treatment circulating tumor DNA (ctDNA) samples collected from patients enrolled in the study were analyzed by next generation sequencing. Somatic putative CHIP mutations and cases with mutation variant allele frequency (VAF) < 0.3% in circulating free DNA at baseline were excluded. Molecular response (MR) was defined as at least 50% reduction of VAF. Results: Molecular data were generated from archival biopsies collected for 33/55 patients and ctDNA samples from 55/55 patients enrolled in the study. High impact mutations were detected in ARID1A (N=10), ATM (N=5), ATRX (N=3), BRCA1/2 (N=13), and other homologous recombination-related genes (N=5). MRs were observed in 11/34 (32%) patients treated with more than 130 mg QD, none were observed in the 10 patients treated with lower doses. The MRs were enriched in patients with ovarian (3/8, 38%), prostate (4/8, 50%), and breast cancer (1/3, 33%), while less frequent (3/15, 25%) in other indications. TP53 mutations were significantly associated with MR, independently of tumor type. Complete MRs were achieved for any mutations in ARID1A (2/7), ATRX (2/5), DAXX (1/3), BRCA1/2 (1/10). A complete MR was seen in a patient with ovarian cancer with prolonged stable disease by RECIST (200 days), and ARID1A mutation in ctDNA. Conclusions: M1774 induced MRs in patients treated with doses in the predicted efficacious concentration range. TP53 alterations were significantly associated with MR. Complete MRs were detected for mutations in the genes ARID1A, ATRX, DAXX that are being tested for participant selection in the ongoing biomarker expansion cohorts of the DDRiver 301 study. 1TA Yap, et al. Ann Oncol. 2022; 33(suppl_7): S197-S224. Citation Format: Anthony W. Tolcher, Timothy A. Yap, Ruth Plummer, Thomas Grombacher, Danyi Wang, Corinna Schaffroth, Christine Hicking, Zoltan Szucs, Giuseppe Locatelli, Johann S. de Bono. Translational analyses of ATR inhibitor M1774 in a Phase I study in patients with solid tumors (DDRiver Solid Tumors 301) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT271.

Background: Ataxia telangiectasia and Rad3-related (ATR) protein kinase plays a critical role in the DNA damage response. M1774, a potent, selective, orally administered ATR inhibitor with antitumor activity in preclinical models, was evaluated in Part A1 of an open-label, single-arm study (NCT04170153) for safety, tolerability, maximum tolerated dose, pharmacokinetics (PK) and pharmacodynamics (PD). M1774 monotherapy in patients with advanced solid tumors was well-tolerated and the totality of evidence, including quantitative model-based analyses, suggested the recommended dose for expansion (RDE) as 180 mg QD 2 weeks on/1 week off.1 Here, we report findings of the M1774 PD and immunophenotyping analyses. Methods: M1774 PD was explored by assessing phosphorylation by ATR of CHK1 (p-CHK1) in tumor and of H2AX (γ-H2AX) in serial blood samples, stimulated ex vivo with the radiomimetic 4-Nitroquinoline N-oxide or Dimethyl sulfoxide as control. A flow cytometry quantitative assay was used to measure γ-H2AX in the CD45+ lymphocytes fraction. The effect of M1774 on the immunophenotype was explored by flow cytometry. Blood samples were collected at baseline, 3 and 24 hours after first M1774 administration on day 1 of cycle 1 for the γ-H2AX analysis, and on Days 1 and 15 of Cycles 1 and 2 before treatment for immunophenotyping. Results: Preclinical tumor tissue-blood bridging PD analyses in a mouse model demonstrated that the inhibition of γ-H2AX in lymphocytes highly correlated with inhibition of p-CHK1 in tumor. Clinical data of γ-H2AX levels and immunophenotyping were generated for the blood samples collected from the 55 participants of Part A1 of the study. Exploratory PK-PD analysis using γ-H2AX levels 3 h post-dose on day 1 across the doses predicted target inhibition >80% for doses ≥130 mg, suggesting target engagement. The levels of ɣ-H2AX at 24 h after first dose intake were variable and mean levels rebounded to baseline value. M1774 treatment did not cause any significant and consistent change in the levels of all explored immune cell subsets at the tested dose levels, including myeloid-derived suppressor cells, T and B lymphocytes, monocytes, and natural killer cells. Conclusions: PD analyses showed that M1774 efficiently inhibited ATR at the RDE without impacting the immunophenotype. 1TA Yap, et al. Ann Oncol. 2022; 33(suppl_7): S197-S224. Citation Format: Ruth Plummer, Anthony W. Tolcher, Timothy A. Yap, Giuseppe Sessa, Jatinder K. Mukker, Annick Seithel-Keuth, Christine Hicking, Zoltan Szucs, Ioannis Gounaris, Giuseppe Locatelli, Johann S. de Bono. Pharmacodynamic and immunophenotyping analyses of ATR inhibitor M1774 in a Phase I study in patients with solid tumors (DDRiver Solid Tumors 301) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT272.

Background Ductal carcinoma in situ (DCIS) is a non-invasive form of early breast cancer, with a poorly understood natural history of invasive transformation. Necrosis is a well-recognized adverse prognostic feature of DCIS, and non-invasive detection of its presence and spatial extent could provide information not obtainable by biopsy. We describe here imaging of the distribution and extent of comedo-type necrosis in a model of human DCIS using C2Am, an imaging agent that binds to the phosphatidylserine exposed by necrotic cells. Methods We used an established xenograft model of human DCIS that mimics the histopathological features of the disease. Planar near-infrared and optoacoustic imaging, using fluorescently labeled C2Am, were used to image non-invasively the presence and extent of lesion necrosis. Results C2Am showed specific and sensitive binding to necrotic areas in DCIS tissue, detectable both in vivo and ex vivo. The imaging signal generated in vivo using near-infrared (NIR) fluorescence imaging was up to 6-fold higher in DCIS lesions than in surrounding fat pad or skin tissue. There was a correlation between the C2Am NIR fluorescence (Pearson R = 0.783, P = 0.0125) and optoacoustic signals (R > 0.875, P Conclusions C2Am is a targeted multi-modal imaging agent that could complement current anatomical imaging methods for detecting DCIS. Imaging the presence and spatial extent of necrosis may give better prognostic information than that obtained by biopsy alone.

Few studies describe supportive care needs among young adults (YAs) with cancer ages 25 to 39 using validated questionnaires. Previous findings identified the need for psychological and information support and suggest that gender, age, psychological distress, and coping may be associated with greater need for this support. To substantiate these findings, this study aimed to (1) describe the supportive care needs of YAs in each domain of the Supportive Care Needs Survey and (2) explore the relationship between unmet supportive care needs and clinical and demographic factors, health-related quality of life, psychological distress, illness cognitions, and service needs using latent class analysis. Clinical teams from six hospitals in England invited eligible patients to a cross-sectional survey by post. A total of 317 participants completed the survey online or on paper. YAs expressed the most need in the psychological and sexuality domains. Using latent class analysis, we identified three classes of YAs based on level of supportive care need: no need (53.3%), low need (28.3%), and moderate need (18.4%). In each class, median domain scores in each domain were similar. Low and moderate need classes were associated with worse health-related quality of life and greater helplessness. Unmet service needs were associated with the moderate-need class only. Patients with unmet supportive care needs should be offered holistic care across supportive care domains.

Additional file 1: Figure S1 Fluorescence imaging (a) of C2Am and iC2Am standard solutions. Excitation (dashed) and emission (filled) profiles (b) of iC2Am-650 (Ex/Em: 652|672 nm, red, left) and C2Am-750 (Ex/Em: 753|783 nm, brown, right). Serial dilutions (decreasing concentration, left to right) of the imaging probes (c, e) were imaged on an IVIS200™ system and the mean fluorescence intensity (in radiant efficiency) correlated with probe concentration, in the far red (d) and near infra-red NIR (f), for C2Am (open circles) and iC2Am (closed squares). iC2Am fluorescence (d) in the far-red (black squares) was minimal (ca. 10% of that of C2Am, open circles). C2Am fluorescence (f) in the NIR was undetectable. Fluorescence intensities (g) of C2Am-650 (in the far-red, open circles in g, data in 2nd row of c) and iC2Am-750 (in the NIR, closed squares in g, data in the top row of e) were identical at all concentrations. A 1:1 molar mixture (h) of C2Am|iC2Am (c, e, lower row) was also imaged in the far-red (open circles) and NIR (closed squares) showing equivalent readouts at all concentrations, in the range 40-2,500 nM. Figure S2. Single wavelength OA images of (a) phantoms (b) and in vivo tumor models are illustrated with the regions of interest (ROIs) used for the data analysis outlined. (c) OA spectra of iC2Am and C2Am molecules were obtained from multispectral imaging of the probes using tissue mimicking phantoms.

Contains fulltext : 235257.pdf (Publisher’s version ) (Open Access) AIMS: Adolescents and young adults aged 15-39 years with cancer face unique medical, practical and psychosocial issues. In the UK, principal treatment centres and programmes have been designed to care for teenage and young adult patients aged 13-24 years in an age-appropriate manner. However, for young adults (YAs) aged 25-39 years with cancer, little access to age-specific support is available. The aim of this study was to examine this possible gap by qualitatively exploring YA care experiences, involving patients as research partners in the analysis to ensure robust results. MATERIALS AND METHODS: We conducted a phenomenological qualitative study with YAs diagnosed with any cancer type between ages 25 and 39 years old in the last 5 years. Participants took part in interviews or focus groups and data were analysed using inductive thematic analysis. Results were shaped in an iterative process with the initial coders and four YA patients who did not participate in the study to improve the rigor of the results. RESULTS: Sixty-five YAs with a range of tumour types participated. We identified seven themes and 13 subthemes. YAs found navigating the healthcare system difficult and commonly experienced prolonged diagnostic pathways. Participants felt under-informed about clinical details and the long-term implications of side-effects on daily life. YAs found online resources overwhelming but also a source of information and treatment support. Some patients regretted not discussing fertility before cancer treatment or felt uninformed or rushed when making fertility preservation decisions. A lack of age-tailored content or age-specific groups deterred YAs from accessing psychological support and rehabilitation services. CONCLUSIONS: YAs with cancer may miss some benefits provided to teenagers and young adults in age-tailored cancer services. Improving services for YAs in adult settings should focus on provision of age-specific information and access to existing relevant support.

GluCAB is a newly synthesised macrocyclic radioligand designed to bind in vivo to albumin (HSA) for the purpose of development as a dual-targeting oncological theranostic agent. Subsequent to its synthesis and 64Cu-radiolabelling, this radioligand has show a prolonged circulation time in healthy mice but with appropriate systemic clearance within 24 h. This radioligand meets the criteria to be further investigated for tumour targeting and uptake.

Sarcoma Unit, Royal Marsden Hospital, London, SW3 6JJ, UK *Author for correspondence: Tel.: +44 020 7808 2137; Fax: +44 207 808 2113; robin.jones@rmh.nhs.uk

A method to produce (117m)Sn radionuclide using accelerator production route is described. A new method is proposed to separate the (117m)Sn. Specific activities and thick target yield for (116)Cd(α,3n)(117m)Sn reaction at E(α)=35MeV bombarding energy were determined. The estimated production yield of (117m)Sn was 37.5kBq/μAh for 13.16 mg/cm(2) natural cadmium-oxide target and 410 kBq/μAh for 11.07 mg/cm(2) highly enriched (95%) (116)CdO target. The method developed for separation of (117m)Sn from Cd using anion-exchange resin (Dowex -1×8, fluorine form, 400 mesh) can achieve 98% radiochemical yield of (117m)Sn with more than 99% radionuclidic purity. The estimated specific activity is 2.4 GBq/mg that can be reached with the used irradiation conditions.

The use of radionuclides as potential therapeutic radiopharmaceuticals is increasingly investigated. An important aspect is the delivery of the radionuclide to the target, i.e. the radionuclide is not lost from the chelating agent. For in vivo generators, it is not only the log K of complexation between the metal ion and the chelator that is important, but also whether the daughter radionuclide stays inside the chelator after decay of the parent radionuclide. In our previous work, we showed that the classical recoil effect is only applicable for decays with a Q value higher than 0.6 MeV (in the atomic mass range around 100). However, Zhernosekov et al. [1] published a result for140Nd/140Pr (Q = 0.222 MeV) which indicated that >95% of the daughter (140Pr) was lost by a DOTA chelator upon decay of140Nd. The authors ascribed this to the & ldquo;post-effect”. Their experiment was repeated with the166Dy/166Ho generator to ascertain whether our calculations were correct. It was found that 72% of the daughter (166Ho) was liberated from the DOTA chelator, indicating that the “post effect” does exist in contrast to our recoil calculations. Upon further investigation, we determined that one should not only consider recoil energy levels but also the mode of decay which was able to explain the partial recoil found for166Dy/166Ho. It is concluded for the166Dy/166Ho system that the low recoil energy of the daughter nucleus166Ho is not a sufficient reason to rule out release of the nuclide from chelators. On the other hand, we found that the ratio of the166Ho that gets released corresponds to the ratio of relaxation of Ho atoms via the Auger process.

Phenylacetate has been reported to have a potent anti-proliferative and anti-differentiating effect in haematological malignancies and in solid tumours at non-toxic concentrations. This study is a preliminary investigation into the potential of 4-iodophenylacetic acid radiolabelled by 131I as a radiopharmaceutical equivalent. The radiolabelling by isotope exchange gave a radiochemical yield of 53±6%, and a radiochemical purity of 97.8±1.2% as qualified by HPLC. The product contained 4% ester by-product and is suitable for studies in animals. Copyright © 2010 John Wiley & Sons, Ltd.

Gastrointestinal stromal tumours (GISTs) represent a very exciting tumour entity for the medical oncologist. There has been extensive clinical and preclinical research dissecting the natural behaviour, molecular landscape and therapeutic responsiveness of this rare mesenchymal tumour. Various molecular subtypes of GIST have a differing prognostic and predictive relevance in the state of the art management of the disease. Emerging mature clinical trial data gathered over the last one and half decade provided substantial molecular profiling information in understanding the success and eventual failure of treatment. In our review of the most relevant literature we aim to guide the clinician in tailoring neoadjuvant, adjuvant and palliative treatment of GIST alongside the different, now well established molecular subgroups of GISTs.

The use of Auger emitters as potential radiopharmaceuticals is being increasingly investigated. One of the radionuclides of interest is 103m Rh, which can be produced from 103 Ru or 103 Pd in an in vivo generator. A potential problem, however, is the recoil of the 103m Rh out of the carrier molecule and even out of the target cell. In order to determine the likelihood of this happening in the 103 Pd/ 103m Rh, case calculations were made to prove that this does not happen. The equations were generalised for all radionuclides with an atomic mass of 10–240 as a tool for determining the recoil threshold of any β-emitting radionuclide.

The use of Auger emitters as potential radiopharmaceuticals is increasingly investigated. One such radionuclide of interest is (103m)Rh. This can be produced from (103)Ru or from (103)Pd in an in vivo generator. A potential problem with this concept is the recoil of the (103m)Rh out of the carrier molecule and even out of the target cell. In order to determine whether this would happen in the (103)Pd/(103m)Rh case calculations were done to prove that this does not happen. From theoretical considerations it seems that the (103)Pd/(103m)Rh in vivo generator system would be possible.

Contains fulltext : 200567.pdf (Publisher’s version ) (Open Access) Background: One of the commonly used systemic agents for the treatment of aggressive fibromatosis is the anti-oestrogen drug tamoxifen. However, data on efficacy and optimum methods of response assessment are limited, consisting mainly of small case series and reports. Methods: A retrospective database was used to identify consecutive patients diagnosed with aggressive fibromatosis (AF) and treated with tamoxifen plus/minus non-steroidal anti-inflammatory drugs at our tertiary referral centre between 2007 and 2014. MRI and symptom changes were recorded. Results: Thirty-two patients (13 male 19 female, median age 41 years) were included. Median duration of treatment with tamoxifen was 316 days. Of 9 patients with progressive disease by RECIST 1.1 (28%): 4 patients experienced worsening symptoms; 3 patients had improved symptoms and 2 had no change in symptoms. Of 22 patients with stable disease (69%): 11 had no change in symptoms; 6 had improved symptoms and 5 patients had worsening symptoms. One patient achieved a partial response with improved symptoms. Conclusions: No relationship was identified between symptomatic benefit and response by RECIST 1.1 on MRI. Prospective studies in AF should incorporate endpoints focusing on patient symptoms.

The biodistribution of an N2 N2 ' tetradentate gold(III) chelate, which is known to be cytotoxic towards a range of human cancer cell lines, was determined by a radiolabelled equivalent of the compound. The (198) Au-labelled gold(III) chelate of a bis(pyrrolide-imine) Schiff base ligand with a three-carbon di(azomethine) linkage was successfully synthesised with a high radiochemical yield of 73% and radiochemical purity of95%. The high energy γ-ray emitted by the (198) Au nucleus was used to follow the biodistribution of the compound in vivo in six male Sprague Dawley rats on a gamma camera. The log Po/w value of the (nat) Au analogue, -1.92(2), showed that the compound is hydrophilic and therefore likely to largely remain in the blood pool. This was confirmed by the biodistribution study, which showed 21% of the injected dose (ID) remained in the blood pool 4.5 h after injection. This decreased to 10.8% over a 24-h period. The activity measured in the lungs, 1.48%ID/g, remained relatively constant over a 24-h period suggesting that the complex had accumulated in the lungs in the form of particulates, and could not be cleared by the test subjects. The t½ for the heart and lungs was greater than 24 h. Excretion of the test compound is seemingly via the kidneys, but is slow with approximately 30% of the ID excreted within 24 h.

11033Background: Treatment of patients with metastatic Ewing sarcoma (ES) remains a challenge. Pre-clinical studies and small retrospective series, mainly including pediatric patients, have demonst...

The pathogenesis of breast cancer is polygenic. Exploring the involvement of different onco- and tumor suppressor genes, and combinations of these genes, in early breast cancer formation is important for understanding the natural history of the disease. Preclinical studies of the fundamental biological and metabolic changes that occur during breast oncogenesis in currently available transgenic mouse models are limited by the requirement for tissue-specific promoters and the random nature of tumor formation. The mouse mammary gland is a unique organ in that most of its development occurs after birth. Moreover, isolated mammary epithelial cells (MECs) have the capacity to regenerate a functional gland upon orthotopic transplantation into the cleared fat pad of a syngeneic recipient. We describe here a new transplantation system using pure MECs derived from genetically engineered mice harboring floxed oncogenes. First we selected in vitro for a stromal and hematopoietic cell-free MEC preparation. In the MEC donor transgenic strains the activation of oncogenes (K-Ras, c-Myc) or the deletion of tumor suppressors (p53) is dependent on Cre recombinase expression (Cre-lox system). Using an adenoviral Cre-recombinase vector we activated these oncogenic changes in isolated MECs. Colony formation assays demonstrated the viability of these mixed transduced/non-transduced MEC populations. Following transplantation into the cleared fat pad of syngeneic mice the transduced MECs preserved their fat pad repopulating and duct forming potential and the induced oncogenic changes resulted in mammary tumor formation. This proposed system offers tissue specific promoter-free and lactation independent spatial control of oncogenic events in the epithelial cell compartment of breast ducts. Citation Format: Zoltan Szucs, Michael D. Prater, John Stingl, Kevin M. Brindle. A novel orthotopic mammary epithelial cell (MEC) transplantation model of breast cancer formation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 78. doi:10.1158/1538-7445.AM2014-78