Despite evidence for a role for prolactin signaling in breast and prostate tumorigenesis, a prolactin receptor-binding monoclonal antibody has not produced clinical efficacy.Increased serum prolactin levels may be a biomarker for prolactin receptor inhibition.Results from the pharmacokinetic and pharmacodynamics (PD) studies suggest that inappropriately long dosing intervals and insufficient exposure to LFA102 may have resulted in lack of antitumor efficacy.Based on preclinical data, combination therapy of LFA102 with those novel agents targeting hormonal pathways in metastatic castration-resistant prostate cancer and metastatic breast cancer is promising.Given the PD evidence of prolactin receptor blockade by LFA102, this drug has the potential to be used in conditions such as hyperprolactinemia that are associated with high prolactin levels.
Prolactin receptor (PRLR) signaling is implicated in breast and prostate cancer. LFA102, a humanized monoclonal antibody (mAb) that binds to and inhibits the PRLR, has exhibited promising preclinical antitumor activity.
Patients with PRLR-positive metastatic breast cancer (MBC) or metastatic castration-resistant prostate cancer (mCRPC) received doses of LFA102 at 3-60 mg/kg intravenously once every 4 weeks. Objectives were to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) to investigate the safety/tolerability of LFA102 and to assess pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity.
A total of 73 patients were enrolled at 5 dose levels. The MTD was not reached because of lack of dose-limiting toxicities. The RDE was established at 60 mg/kg based on PK and PD analysis and safety data. The most common all-cause adverse events (AEs) were fatigue (44%) and nausea (33%) regardless of relationship. Grade 3/4 AEs reported to be related to LFA102 occurred in 4% of patients. LFA102 exposure increased approximately dose proportionally across the doses tested. Serum prolactin levels increased in response to LFA102 administration, suggesting its potential as a biomarker for PRLR inhibition. No antitumor activity was detected.
Treatment with LFA102 was safe and well tolerated, but did not show antitumor activity as monotherapy at the doses tested.
©AlphaMed Press; the data published online to support this summary is the property of the authors.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

On April 20, 2016 Syros Pharmaceuticals reported that SY-1365, a first-in-class potent and selective cyclin-dependent kinase 7 (CDK7) inhibitor, was observed to induce durable tumor regression and prolong survival in in vivo models of acute myeloid leukemia (AML) (Press release, Syros Pharmaceuticals, APR 20, 2016, View Source [SID:1234511184]). These data were presented at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans. Based on the strong efficacy and safety data, Syros selected SY-1365 as its development candidate and plans to file an Investigational New Drug (IND) application with the U.S. Food and Drug Administration in the second half of 2016 with the goal of initiating a Phase 1/2 clinical study in acute leukemia in the first half of 2017.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"Up until now, creating medicines to control important disease causing transcription factors has been a major challenge in cancer drug development. SY-1365, our first-in-class CDK7 inhibitor, highlights the potential of our pioneering platform to produce drugs that can selectively modulate these transcription factors," said Nancy Simonian, M.D., Chief Executive of Syros. "Certain hematologic and solid tumor cancers, including AML, are dependent on transcription factors for their growth and survival and have been shown to be particularly dependent on CDK7. Results from preclinical studies demonstrate that SY- 1365 lowers the levels of these disease causing transcription factors and, in so doing, may treat diseases that have eluded other genomics-based approaches and provide a profound and durable benefit for patients with these difficult-to-treat cancers."

In the preclinical studies presented at AACR (Free AACR Whitepaper), SY-1365 was observed to preferentially kill cancer cells over non-cancerous cells and significantly prolong survival in patient-derived xenograft (PDX) models of AML. In the in vitro and in vivo studies, SY-1365 induced:

Tumor regression in 100 percent of treated mice in a cell-line derived xenograft model of AML; tumor regression was maintained through the end of the 38-day study.

Strong survival benefit, with 80 percent of treated mice alive at the end of the 8- week study in a PDX model of treatment-resistant AML; by contrast, none of the untreated mice survived beyond 4-1/2 weeks.

Rapid and dose-dependent apoptosis in AML cell lines treated with SY-1365 while having little to no effect on non-cancerous cells.
Potent and selective inhibition of CDK7, with only six other kinases, none of which are in the CDK family, exhibiting greater than 90 percent binding when profiled across a panel of 468 kinases at a concentration of 1μM.

Minimal effect on blood cell counts in in vivo models, including white blood cells, lymphocytes, neutrophils and reticulocytes, demonstrating a more favorable profile than a non-selective CDK inhibitor.

Reduced expression of cancer-contributing genes associated with specialized regulatory regions of DNA known as super-enhancers, including transcription factors and the oncogenes MYB and MYC, in an AML cell line.

Synergistic activity when combined with other targeted agents in AML, including Flt3, Bcl-2 and pan-Brd inhibitors.

Syros’ selective CDK7 inhibitors, including SY-1365, have been observed to delay tumor progression in additional in vivo models of transcriptionally addicted cancers, including acute lymphoblastic leukemia (ALL), MYCN-amplified neuroblastoma, small cell lung cancer and triple negative breast cancer.

On April 20, 2016 Immune Therapeutics Inc., (OTC-QB: IMUN), reported that they have signed a binding Letter of Intent to acquire Chinese Chimeric Super Antigen Receptor T cell (CAR-T) cocktail therapy, Immuno-Oncology patents (pending), manufacturing technology, and clinical data of the aforementioned therapies from Super-T Cell Cancer Company ("STCC") a newly formed corporation (Filing, 8-K, TNI BioTech, APR 20, 2016, View Source [SID:1234511271]).

"This CAR-T cell technology licensing further accelerates IMUN’s growth in the Immuno-Oncology field as we evaluate paths to commercialization both in China and other Emerging Markets," commented Christopher Pearce Chief Operating Officer.

CAR-T cell therapy involves engineering cancer patients’ own immune cells to recognize and attack cancer tumors. CAR-T therapy has great potential to improve patient-specific cancer therapy in a profound way. Numerous studies have implicated regulatory T cells as key mediators in the creation of an immunosuppressed microenvironment that enables tumors to escape attack by the host immune system. The Super CAR –T Cocktail therapy has shown promise in early human clinical trials for the treatment of blood cancer, renal, cervical and hepatic cancer.

"We are very impressed by the quality of the work done by Professor Shan and his team, and are excited by the safe and efficacious profile of this novel CAR-T cocktail therapy for cancerous diseases. This is the beginning of a long-term strategic partnership between IMUN and STCC. Together, we will expeditiously continue our quest in developing more affordable, safer, and more effective cancer immunotherapy programs," said Noreen Griffin, Chief Executive Officer of Immune Therapeutics, Inc.

The need in China for new affordable therapies is critical. It is predicted that there will be about 4,292,000 newly diagnosed invasive cancer cases in 2016, corresponding to almost 12,000 new cancer diagnoses on average each day. IMUN believes that once approved it could capture 5% of the market in the first year.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Up to one third of ovarian cancer patients are intrinsically resistant to platinum-based treatment. However, predictive and therapeutic strategies are lacking due to a poor understanding of the underlying molecular mechanisms. This study aimed to identify key molecular characteristics that are associated with primary chemoresistance in epithelial ovarian cancers.
Gene expression profiling was performed on a discovery set of 85 ovarian tumors with clinically well-defined response to chemotherapies as well as on an independent validation dataset containing 138 ovarian patients from the chemotreatment arm of the ICON7 trial.
We identified a distinct "reactive stroma" gene signature that is specifically associated with primary chemoresistant tumors and was further upregulated in posttreatment recurrent tumors. Immunohistochemistry (IHC) and RNA in situ hybridization (RNA ISH) analyses on three of the highest-ranked signature genes (POSTN, LOX, and FAP) confirmed that modulation of the reactive stroma signature genes within the peritumoral stromal compartments was specifically associated with the clinical chemoresistance. Consistent with these findings, chemosensitive ovarian cells grown in the presence of recombinant POSTN promoted resistance to carboplatin and paclitaxel treatment in vitro. Finally, we validated the reactive stroma signature in an independent dataset and demonstrated that a high POSTN expression level predicts shorter progression-free survival following first-line chemotherapy.
Our findings highlight the important interplay between cancer and the tumor microenvironment in ovarian cancer biology and treatment. The identified reactive stromal components in this study provide a molecular basis to the further development of novel diagnostic and therapeutic strategies for overcoming chemoresistance in ovarian cancer.
©2015 American Association for Cancer Research (AACR) (Free AACR Whitepaper).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

On April 20, 2016 CytRx Corporation (NASDAQ: CYTR), a biopharmaceutical research and development company specializing in oncology, reported that three aldoxorubicin clinical trials have been accepted for poster presentations during the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting being held at McCormick Place in Chicago, Illinois, from June, 3-7, 2016 (Press release, CytRx, APR 20, 2016, View Source;p=RssLanding&cat=news&id=2158694 [SID:1234511140]). The three clinical trials to be presented are:

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Title: Phase 2 study of aldoxorubicin in relapsed glioblastoma
Date/Time: June 4, 2016 1:00pm-5:00pm
Poster Session: Central Nervous System Tumors; Abstract 2027

Title: Phase 1b study of aldoxorubicin + gemcitabine in metastatic solid tumors
Date/Time: June 5, 2016 8:00am-11:30am
Poster Session: Developmental Therapeutics – Clinical Pharmacology and Experimental Therapeutics; Abstract: 2523

Title: Treatment of HIV-associated Kaposi’s sarcoma with aldoxorubicin
Date/Time: June 6, 2016 8:00am-11:30am
Poster Session: Sarcoma; Abstract: 11038

"Presenting the results from these three clinical trials at the ASCO (Free ASCO Whitepaper) Annual Meeting demonstrates the broad potential for aldoxorubicin and should raise awareness among oncologists," said Daniel Levitt, M.D., Ph.D., CytRx’s EVP and Chief Medical Officer. "Based on its unique ability to selectively bind serum albumin and preferentially release drug at the tumor site, aldoxorubicin has now shown clinical anti-cancer activity in several tumor types including our lead indication of advanced soft tissue sarcomas for which we expect top-line data in June from our pivotal Phase 3 trial."

Aldoxorubicin is CytRx’s lead anti-cancer drug candidate in clinical development utilizing its LADRTM (Linker Activated Drug Release) technology. A global, pivotal Phase 3 trial in patients with relapsed or refractory soft tissue sarcomas has fully enrolled and top-line results for the primary endpoint of progression-free survival are expected in June 2016. The trial is being conducted under a Special Protocol Assessment granted by the FDA. In addition, CytRx is conducting a randomized Phase 2b clinical trial in patients with second-line small cell lung cancer comparing aldoxorubicin topotecan. CytRx has completed enrollment of a Phase 2 trial with aldoxorubicin for patients with relapsed glioblastoma and continues to follow patients for survival. CytRx also conducted a Phase 2 trial with low doses of aldoxorubicin in patients with HIV-related Kaposi’s sarcoma. Aldoxorubicin is currently being tested in two Phase 1b trials in combination with other chemotherapies. The first trial is in combination with gemcitabine for metastatic solid tumors, and the second trial is in combination with ifosfamide as a first-line treatment for patients with soft tissue and bone sarcomas.

About Aldoxorubicin

The widely used chemotherapeutic agent doxorubicin is delivered systemically and is highly toxic, which limits its dose to a level below its maximum therapeutic benefit. Doxorubicin also is associated with many side effects, especially the potential for damage to heart muscle at cumulative doses greater than 450 mg/m2. Aldoxorubicin combines doxorubicin with a novel single-molecule linker that binds directly and specifically to circulating albumin, the most plentiful protein in the bloodstream. Protein-hungry tumors concentrate albumin, thus increasing the delivery of the linker molecule with the attached doxorubicin to tumor sites. In the acidic environment of the tumor, but not the neutral environment of healthy tissues, doxorubicin is released. This allows for greater doses (3 ½ to 4 times) of doxorubicin to be administered while reducing its toxic side effects. In studies thus far there has been no evidence of clinically significant effects of aldoxorubicin on heart muscle, even at cumulative doses of drug well in excess of 2,000 mg/m2.