On November 24, 2015 CTI BioPharma Corp. (CTI BioPharma or the Company) (NASDAQ and MTA: CTIC) reported that the United Kingdom’s National Cancer Research Institute (NCRI) Haematological Oncology Clinical Studies Group has chosen to advance tosedostat, the Company’s investigative oral aminopeptidase inhibitor, to the second stage of a randomized clinical trial of low-dose cytarabine plus or minus tosedostat in older patients with Acute Myeloid Leukemia (AML) or high risk Myelodysplastic Syndrome (MDS) (Press release, CTI BioPharma, NOV 23, 2015, View Source;p=RssLanding&cat=news&id=2116992 [SID:1234508332]). The AML Less Intensive (LI-1) trial is designed as a "Pick-a-Winner" trial to be able to simultaneously test a number of promising agents added to standard therapy with low-dose cytarabine in older patients with AML or MDS who are unfit for standard aggressive induction therapy. Nine regimens have been tested in the Pick-a-Winner program, of which only 4, including tosedostat, have passed the initial hurdle for progression (which requires evidence of an improvement in remission rate with acceptable safety). The ultimate aim of the trial is to identify treatments that can double the 2-year survival of patients in this group. Based on the randomized Phase 2 interim analysis, the trial management group determined that tosedostat should proceed to the next stage of the study. It is anticipated that an additional 110 patients will be required in such phase. A further evaluation will take place before the intended expansion to a 400 patient Phase 3 trial.

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Tosedostat is a potential first-in-class selective inhibitor of aminopeptidases, which are enzymes required by some tumor cells, but not normal cells, to provide a source of amino acids necessary for growth and tumor cell survival.

"A large portion of older patients and patients with comorbid conditions are poorly suited for conventional intensive chemotherapy due to a high rate of treatment-related mortality. For these patients, there is a significant unmet need for effective and well tolerated alternative therapies," said Jack Singer, M.D., Chief Scientific Officer of CTI BioPharma. "We are pleased that tosedostat has been selected to continue in this trial and is moving forward to the next stage. Tosedostat has demonstrated encouraging clinical activity in three prior Phase 2 studies in both first-line AML in older patients and in patients who relapsed following standard therapies. Tosedostat is an oral agent given once daily on an outpatient basis that has not been associated with drug-related blood count suppression."

About the LI-1 Trial
In this Phase 2/3 trial, referred to as the AML Less Intensive (LI-1) trial, patients are randomized to standard treatment with low dose cytarabine, versus several investigational treatments – each usually in combination with low dose cytarabine. This is called a "Pick-a-Winner" trial design. Under this design, the Phase 2 portion of the trial initially randomized 50 patients per arm, and, if the complete response rate of cytarabine plus novel therapy appeared satisfactory, the randomization continues to the next stage usually with an additional 50 patients per arm. There is then a further assessment by the data monitoring committee to allow the trial to continue to the final stage in which case up to a total of approximately 200 patients per arm would be enrolled. Overall survival will serve as the primary endpoint of the trial. The NCRI Haematological Oncology Clinical Studies Group under the sponsorship of Cardiff University is conducting the trial.

About Tosedostat
Tosedostat is an oral aminopeptidase inhibitor that has demonstrated anti-tumor responses in blood-related cancers and solid tumors in Phase 1-2 clinical trials. Tosedostat is currently being evaluated in multiple Phase 2 clinical trials for the treatment of patients with AML or high-risk MDS. Tosedostat is not approved or commercially available.

About Acute Myeloid Leukemia and Myelodysplastic Syndrome
AML is the most common acute leukemia affecting adults, and its incidence increases with age. In older patients, AML may occur de novo or secondary to prior anti-cancer therapy, or from progression of other diseases, such as myelodysplasia. AML is a cancer characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. AML is the most common acute leukemia affecting adults, and its incidence increases with age.1 The symptoms of AML are caused by the replacement of normal bone marrow with leukemic cells, which causes a drop in red blood cells, platelets, and normal white blood cells, leading to infections and bleeding. AML progresses rapidly and is typically fatal within weeks or months if left untreated. In 2015, approximately 20,830 new cases of AML are expected to be diagnosed in the United States and an estimated 10,460 are expected to die from the disease.2 While AML may occur at any age, adults at least 60 years of age are more likely than younger people to develop the disease.2 Although a substantial proportion of younger individuals who develop AML can be cured, AML in the elderly typically responds poorly to standard therapy with few complete remissions.

AML may develop from the progression of other diseases, such as MDS. MDS are a group of diverse bone marrow disorders in which the bone marrow does not produce enough healthy blood cells. MDS is often referred to as a "bone marrow failure disorder."

On November 23, 2015 The U.S. Food and Drug Administration reported that it approved Opdivo (nivolumab) to treat patients with advanced (metastatic) renal cell carcinoma, a form of kidney cancer, who have received a certain type of prior therapy.
"Opdivo provides an important therapy option for patients with renal cell carcinoma," said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research (Press release, , NOV 23, 2015, View Source [SID:1234508328]). "It is one of few therapies that have demonstrated the ability to extend patients’ survival in treating this disease." Torisel (temsirolimus), approved in 2007, is the only other FDA-approved therapy that has demonstrated overall survival in renal cell cancer.

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Renal cell carcinoma is the most common form of kidney cancer in adults and forms in the tissues of the kidney that make urine. The National Cancer Institute estimates 61,560 new cases and 14,080 deaths from kidney and renal pelvis cancer in the United States this year.

"Additionally, Opdivo’s extended indication, from melanoma and non-small cell lung cancer to renal cell cancer, demonstrates how immune therapies can benefit patients across a wide range of tumors," continued Dr. Pazdur.

Opdivo works by targeting the cellular pathway known as PD-1/PD-L1 (proteins found on the body’s immune cells and some cancer cells). By blocking this pathway, Opdivo may help the body’s immune system fight cancer cells. Opdivo is intended for use in renal cell carcinoma in patients who have received prior anti-angiogenic therapy (treatments that interfere with the blood vessels that contribute to the growth of cancerous cells).

The safety and efficacy of Opdivo for this use were demonstrated in an open-label, randomized study of 821 patients with advanced renal cell carcinoma whose disease worsened during or after treatment with an anti-angiogenic agent. Patients were treated with Opdivo or another type of kidney cancer treatment called everolimus (marketed as Afinitor). Those treated with Opdivo lived an average of 25 months after starting treatment compared to 19.6 months in those treated with Afinitor. This effect was observed regardless of the PD-L1 expression level of patients’ renal cell tumors. Additionally, 21.5 percent of those treated with Opdivo experienced a complete or partial shrinkage of their tumors, which lasted an average of 23 months, compared to 3.9 percent of those taking Afinitor, lasting an average of 13.7 months.

The most common side effects of Opdivo for this use are conditions relating to abnormal weakness or lack of energy (asthenic conditions), cough, nausea, rash, difficulty breathing (dyspnea), diarrhea, constipation, decreased appetite, back pain and joint pain (arthralgia).

Opdivo also has the potential to cause serious side effects that result from the immune system effect of Opdivo (known as "immune-mediated side effects"). These severe immune-mediated side effects involve healthy organs, including the lung, colon, liver, kidneys, hormone-producing glands and the brain.

The FDA granted the Opdivo application a breakthrough therapy designation, fast track designation, and priority review status. These are distinct programs intended to facilitate and expedite the development and review of certain new drugs in light of their potential to benefit patients with serious or life-threatening conditions.

Opdivo is marketed by Bristol-Myers Squibb based in Princeton, New Jersey. Torisel is marketed by Pfizer, based in New York, New York. Afinitor is marketed by Novartis Pharmaceuticals of East Hanover, New Jersey.

On November 23, 2015 NewLink Genetics Corporation (NLNK), a biopharmaceutical company at the forefront of discovering, developing and commercializing novel immuno-oncology product candidates, including both cellular immunotherapy and checkpoint inhibitor platforms, to improve the lives of patients with cancer, reported a trial update from a Phase 1b/2 study of indoximod in combination with temozolomide presented on November 20 at the 20th Annual Scientific Meeting of the Society for Neuro-Oncology in San Antonio, Texas (Press release, NewLink Genetics, NOV 23, 2015, View Source [SID:1234508326]).

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Indoleamine 2,3-dioxygenase (IDO) is a key immuno-modulatory enzyme that allows tumors to thwart the host immune response and therefore is an important research target. IDO is expressed in a large proportion of solid tumors, including 50-90% of glioblastoma tumors. Indoximod is NewLink Genetics’ proprietary product candidate that has shown the potential to interfere with multiple targets within the IDO pathway and thereby to unleash the immune system to fight cancer.

The update presented is from a Phase 1b/2 study of indoximod in combination with temozolomide in patients with advanced glioblastoma who have previously demonstrated that their tumors are refractory to temozolomide. The completed Phase 1b portion of the study, which enrolled 12 patients, continues to show that the combination has an acceptable safety profile, confirming data previously presented. This Phase 1b portion of the study also demonstrated preliminary efficacy of the combination therapy. A six-month progression free survival (PFS) rate of 25% was observed, which compares favorably to the historical rate of 15% for refractory glioblastoma. In addition, the patient previously reported as having achieved a radiographically confirmed partial response (PR) remains on study treatment and has thus far demonstrated a durable response of greater than eight months, with an overall survival on trial of 20 months.

The Phase 2 portion of the study, which aims to determine the preliminary efficacy of the combination therapy, has enrolled 40 of a planned 132 patients as of the data cutoff. Nine of the 40 patients have been enrolled for more than six months and seven are evaluable as to outcome. One of these seven patients has demonstrated a radiographically confirmed PR after previously being refractory to treatment with temozolomide. The objective response occurred after having stable disease on treatment for six months. Of note, the onsets of the two partial responses, one in Phase 1b and one in Phase 2, were delayed, suggesting a possible immunotherapy-based mechanism of response.

"It is encouraging to see some promising early signs of activity of this combination of an immunotherapy with standard chemotherapy in recurrent GBM, which is a disease with huge unmet need," said Howard Colman, MD, PhD, Associate Professor of Neurosurgery and Director of Medical Neuro-Oncology at the Huntsman Cancer Institute at the University of Utah and an author of the study.

"I am particularly impressed with the potential early signals of an immune-mediated effect, as evidenced by the delayed onset and durability of the responses observed," said Olivier Rixe, MD, PhD, Professor of Medicine and Associate Director for Clinical Research at the University of New Mexico Comprehensive Cancer Center and an author of the study. "This is one of the first clinical trials testing an immune checkpoint inhibitor in glioblastoma. It shows that indoximod is the first such therapy to produce an objective response in glioblastoma."

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"We are pleased with the preliminary safety and efficacy data on the combination of indoximod and temozolomide in glioblastoma obtained so far in this study," said Nicholas Vahanian, M.D., President and Chief Medical Officer. "We look forward to learning more about indoximod in our clinical studies in glioblastoma and four other cancer types, as well as about our six other immuno-oncology products currently in clinical testing."

On November 23, 2015 DelMar Pharmaceuticals, Inc. (OTCQX: DMPI) ("DelMar" and the "Company"), a biopharmaceutical company focused on the development and commercialization of new cancer therapies, reported updated data from the fully enrolled 14-patient expansion cohort of the Company’s ongoing Phase II clinical study of VAL-083 (dianhydrogalactitol) in refractory glioblastoma multiforme (GBM) that is being conducted at Sarah Cannon Research Institute, Mayo Clinic, and UCSF Medical Center (Press release, DelMar Pharmaceuticals, NOV 23, 2015, View Source [SID:1234508323]).

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The data were presented at the 20th Annual Scientific Meeting and Education Day of the Society for Neuro-Oncology (SNO) in San Antonio, Texas, held November 19-22, in a poster entitled, "Phase I/II study of Dianhydrogalactitol (VAL-083) In Patients With Recurrent Malignant Glioma." Interested parties can access the poster here.

DelMar will host a conference call and live webcast for investors, analysts and other interested parties today at 4:30 p.m. Eastern Time / 1:30 p.m. Pacific Time to provide a business update and discuss these new data.

"The interim survival data from the Phase II expansion cohort is highly promising and consistent with our observations from the Phase I dose-escalation portion of the trial," stated Jeffrey Bacha, DelMar’s chairman & CEO. "A Kaplan Meyer survival estimate, based on these preliminary interim data, projects a greater than 9-month median survival in refractory GBM patients whose tumors have recurred following both front-line therapy with temozolomide and second-line bevacizumab (Avastin) treatment."

"These results continue to support the potential of VAL-083 to address the significant unmet medical need for these patients who currently have no approved therapeutic options," said Mr. Bacha.

"The Phase II portion of the VAL-083 study in patients with recurrent GBM enrolled very quickly. This rapid enrollment, combined with the enthusiasm we have seen from clinical investigators, is a clear demonstration of the overwhelming unmet medical need for new therapies in the treatment of GBM," stated Mr. Bacha.

"The data from the Phase II cohort of our clinical study continue to show that VAL-083 is well-tolerated at the 40 mg/m2 dosing regimen. This dose previously demonstrated the potential to improve survival outcomes in post-bevacizumab refractory GBM," Mr. Bacha continued. "The expanded Phase II data set support 40 mg/m2 as the appropriate dose for advancement into registration-directed Phase II/III clinical trials with VAL-083 in patients with recurrent GBM."

"Additionally, we have continued to demonstrate that the cytotoxic mechanism of VAL-083 is distinct from other chemotherapies used in the treatment of cancer. We can leverage this new understanding of how VAL-083 attacks the tumor with clinical trial data from previously conducted Phase I and Phase II NCI-sponsored clinical trials that validates VAL-083’s clinical activity against a range of tumor-types to address modern unmet medical needs in the treatment of cancer," added Mr. Bacha.

"In the case of GBM, we have shown that the anti-tumor activity of VAL-083 is independent of MGMT, the resistance mechanism which causes the majority of GBM patients to fail currently available cytotoxic chemotherapy," said Mr. Bacha.

"Taken together with historical and recently demonstrated clinical activity, these results suggest that VAL-083’s distinct anti-cancer mechanism has the potential to overcome chemo-resistance and surpass the standard of care in the treatment of GBM," Mr. Bacha concluded.

DelMar is conducting an open-label, single-arm Phase I/II dose-escalation study with VAL-083 in patients with histologically-confirmed GBM, previously treated with radiation who have failed both front-line therapy temozolomide and second-line Avastin (bevacizumab), and, in most cases, one or more salvage therapies. The study utilized 3+3 dose-escalation design. Patients received VAL-083 on days 1, 2, 3 of a 21-day cycle (ClinicalTrials.gov Identifier NCT01478178) at Sarah Cannon Research Institute, Mayo Clinic, and UCSF Medical Center.

In the Phase I dose-escalation portion of the study, VAL-083 was well tolerated at doses up to 40mg/m2 using a regimen of daily x 3 every 21 days. The 40 mg/m2/d dose exhibited a favorable safety profile, with a trend toward improved survival versus lower doses. Following determination of the maximum tolerated dose (MTD) at 40 mg/m2/d, a 14-patient Phase II expansion cohort was rapidly enrolled at a dose of 40 mg/m2/d on day 1, 2, 3 of a 21 day cycle.

Update on Status of Phase II Expansion Cohort

14 patients have been enrolled in the Phase II expansion cohort and all patients have received at least one cycle of treatment to date.

Safety observations in the Phase II expansion cohort to date are consistent with the Phase I dose-escalation cohort. Generally, observed myelosuppression is mild (Grade 1), with the exception of one patient.

One subject previously treated with CCNU developed Grade 4 thrombocytopenia suggesting patients with prior nitrosourea treatment who may exhibit higher susceptibility to thrombocytopenia. The inclusion criteria were modified to account for this observation.

A Kaplan Meyer survival estimate based on interim analysis of patients enrolled in the Phase II expansion cohort is consistent with observations made in the Phase I dose-escalation portion of the study. This preliminary interim analysis suggests a potentially meaningful survival benefit in this population following treatment with VAL-083 at doses >30 mg/m2/d in comparison to published reports for the same refractory GBM population.

GBM is the most common and deadly form of brain cancer. Standard front-line treatment following surgical resection is temozolomide chemotherapy combined with radiation treatment followed by maintenance therapy with temozolomide. Temozolomide is often ineffective in the majority of GBM patients by O6-methylguanine-DNA-methyltransferase (MGMT), a naturally occurring DNA-repair enzyme causing resistance to treatment. Bevacizumab (Avastin) has been approved as second-line therapy for patients failing front-line therapy; however, data presented at the SNO2015 meeting suggest that bevacizumab treatment does not prolong survival for refractory GBM patients. DelMar has demonstrated that VAL-083’s anti-tumor activity is unaffected by the expression of MGMT, a DNA repair enzyme that is implicated in chemotherapy resistance and poor outcomes in GBM patients following standard front-line treatment with temozolomide.

Taken together with historical and recently demonstrated clinical activity, these data suggest a distinct anti-cancer mechanism for VAL-083 which has the potential to overcome chemo-resistance and surpass the standard of care in the treatment of GBM.

The poster on the clinical trial data presented at SNO may be found on DelMar’s website under View Source

CONFERENCE CALL DETAILS
DelMar is hosting a conference call today at 4:30 p.m. Eastern Time / 1:30 p.m. Pacific Time. For both "listen-only" participants and those who wish to take part in the question and answer portion of the call, the telephone Dial-in Number is (844) 303-8663 (toll-free) with Conference ID 81768802. A link to the webcast and slides will be available on the IR Calendar of the Investors section of the Company’s website at www.delmarpharma.com, and will be archived for 30 days.

About VAL-083
VAL-083 is a "first-in-class," small-molecule chemotherapeutic. In more than 40 Phase I and II clinical studies sponsored by the U.S. National Cancer Institute, VAL-083 demonstrated clinical activity against a range of cancers including lung, brain, cervical, ovarian tumors and leukemia both as a single-agent and in combination with other treatments. VAL-083 is approved in China for the treatment of chronic myelogenous leukemia (CML) and lung cancer, and has received orphan drug designation in Europe and the U.S. for the treatment of malignant gliomas.

VAL-083 is a bi-functional DNA N7 cross-linking agent that crosses the blood-brain barrier that has demonstrated historical clinical activity against a range of cancers, including GBM, in prior NCI-sponsored clinical trials. DelMar has demonstrated that VAL-083 induces phosphorylation of H2AX, a hallmark of double-strand DNA breaks, leading to cell cycle arrest in the late G2/S phase. H2AX is a histone involved in the CHK2 checkpoint activation pathway, a key component of the body’s immune response to DNA damage that activates down-stream signaling ultimately resulting in apoptosis (cancer cell death). Additionally, the cytotoxic activity of VAL-083 appears to be less dependent on wild type p53 in comparison to other chemotherapeutic agents. Alteration in p53 has been correlated with poor patient outcomes in GBM. In particular, gain-of-function mutant p53 is strongly associated with a poor prognosis for overall survival in patients with glioblastoma, potentially by increasing expression of MGMT, a DNA repair enzyme that is implicated in chemotherapy resistance to temozolomide and poor outcomes in GBM patients.

DelMar has previously demonstrated that VAL-083’s anti-tumor activity is unaffected by the expression of MGMT. Taken together with historical and recently demonstrated clinical activity, these data suggest a distinct anti-cancer mechanism for VAL-083 which has the potential to overcome chemo-resistance and surpass the standard of care in the treatment of GBM.

DelMar recently announced the completion of enrollment in a Phase II clinical trial of VAL-083 in refractory GBM. Patients have been enrolled at five clinical centers in the United States: Mayo Clinic (Rochester, MN); UCSF (San Francisco, CA) and three centers associated with the Sarah Cannon Cancer Research Institute (Nashville, TN, Sarasota, FL and Denver, CO).

In the Phase I dose-escalation portion of the study, VAL-083 was well tolerated at doses up to 40mg/m2 using a regimen of daily x 3 every 21 days. Adverse events were typically mild to moderate; no treatment-related serious adverse events reported at doses up to 40 mg/m2. Dose limiting toxicity (DLT) defined by thrombocytopenia (low platelet counts) was observed in two of six (33%) of patients at 50 mg/m2. Generally, DLT-related symptoms resolved rapidly and spontaneously without concomitant treatment, although one patient who presented with hemorrhoids received a platelet transfusion as a precautionary measure.

Sub-group analysis of data from the Phase I dose-escalation portion of the study suggested a dose-dependent and clinically meaningful survival benefit following treatment with VAL-083 in GBM patients whose tumors had progressed following standard treatment with temozolomide, radiotherapy, bevacizumab and a range of salvage therapies.

Patients in a low dose (<5mg/m2) sub-group had a median survival of approximately five (5) months versus median survival of approximately nine (9) months for patients in the therapeutic dose (30mg/m2 & 40mg/m2) sub-group following initiation of VAL-083 treatment. DelMar reported increased survival at 6, 9 and 12 months following initiation of treatment with VAL-083 in the therapeutic dose sub-group compared to the low dose sub-group.

On November 23, 2015 Cyclacel Pharmaceuticals, Inc. (Nasdaq:CYCC) (Nasdaq:CYCCP) ("Cyclacel" or the "Company"), reported the presentation of preclinical data demonstrating that CYC065, a highly-selective, second-generation cyclin dependent kinase (CDK) 2/9 inhibitor prolongs survival in MYCN-addicted neuroblastoma models (Press release, Cyclacel, NOV 23, 2015, View Source [SID:1234508320]). The in vitro and in vivo preclinical data will be presented at the 4th Neuroblastoma Symposium, November 26-27, 2015 in Newcastle Upon Tyne, United Kingdom.

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"MYC activates a major genetic pathway in cancer that is very difficult to target directly," said Spiro Rombotis, Cyclacel’s President and Chief Executive Officer. "CYC065 treatment of MYC-addicted neuroblastoma via CDK2/cyclin E inhibition offers a novel approach to target this critical cancer mechanism. Tumor regression or improved survival is seldom seen in animal models of cancers addicted to MYC proteins, such as MYCN. We are encouraged by the CYC065 data as they add to the growing evidence of the value of CDK inhibition as an innovative approach to treat cancer. Previous data demonstrated that CDK2/9 inhibitors target key molecular features of cancers with poor prognosis, such as cyclin E amplification/overexpression, MLL rearrangements and MYC-amplification/overexpression. We have recently initiated a first-in-human, Phase 1 trial of CYC065 in patients with advanced solid tumors."

The study evaluated the ability of two Cyclacel CDK2/9 inhibitors, CYC065 and CCT68127, to inhibit cell proliferation and induce apoptosis of neuroblastoma cells in vitro and in vivo. In vivo efficacy was evaluated in subcutaneous xenograft models of both MYCN-amplified and non-amplified neuroblastoma cells and the Th-MYCN genetically-engineered mouse model of neuroblastoma. The study showed that neuroblastoma cell lines with MYCN amplification and high MYCN expression levels were sensitive to both CDK2/9 inhibitors. CYC065 and CCT68127 depleted MYCN protein in a time- and dose-dependent manner, blocked neuroblastoma cell proliferation and induced apoptosis. Both CYC065 and CCT68127 resulted in significantly reduced tumor burdens and prolonged survival in MYCN-addicted neuroblastoma models in vivo.

Presentation details:

Presentation title: Orally available small molecule CDK inhibitors CYC065 and CCT68127 prolong survival in MYCN-addicted neuroblastoma models.

Authors: Poon E, Jamin Y, Hakkert A, Hallsworth A, Thway K, Barker K, Sbirkov Y, Pickard L, Urban Z, Almeida G, Tardif N, Webber H, Box G, Valenti M, De Haven Brandon A, Poudel P, Sadanandam A, Eccles S, Robinson SP, Zheleva D, Petrie K, Chesler L.

Location: 4th Neuroblastoma Society Symposium 2015, 26 — 27 November, Newcastle, UK

About MYCN

The MYCN gene encodes a transcription factor that is expressed in fetal brain and neural crest and is critical for normal development of brain and nerve. MYCN is over-expressed in a number of different types of cancer, most notably neuroblastoma, but also including rhabdomyosarcoma, medulloblastoma, astrocytoma, Wilms’ tumor, and small cell lung cancer. Amplification of the MYCN oncogene is the most common genomic alteration in aggressive neuroblastomas and is associated with poor clinical outcome. No drugs that directly target MYCN are available prompting the investigation of indirect approaches such as exploitation of a synthetic lethal relationship between MYCN amplification/overexpression and inhibition of CDK2.

About Neuroblastoma

According to the American Cancer Society, neuroblastoma is the most common cancer in infants less than one year old and it accounts for about six percent of all pediatric cancers or about 700 cases per year. The disease kills one in every seven children diagnosed with it. There are no approved treatments. The presented study demonstrated that CYC065 and CCT68127 target MYCN, and have potent in vitro and in vivo anti-tumor activities, suggesting therapeutic potential in neuroblastoma with amplification of MYCN oncogene.