2018 Zhang Ammonium and arsenic trioxide are potent facilitators of oligonucleotide function when delivered by gymnosis; Xiaowei Zhang, Daniela Castanotto, Xueli Liu, Amotz Shemi and Cy A. Stein, Nucleic Acids Research, 2018 1

Abstract: Oligonucleotide (ON) concentrations employed for therapeutic applications vary widely, but in general are high enough to raise significant concerns for off target effects and cellular toxicity. However, lowering ON concentrations reduces the chances of a therapeutic response, since typically relatively small amounts of ON are taken up by targeted cells in tissue culture. It is therefore imperative to identify new strategies to improve the concentration dependence of ON function. In this work, we have identified ammonium ion (NH4+) as a non-toxic potent enhancer of ON activity in the nucleus and cytoplasm following delivery by gymnosis. NH4
+ is a metabolite that has been extensively employed as diuretic, expectorant, for the treatment of renal calculi and in a variety of other diseases. Enhancement of function can be found in attached and suspension cells, including in difficult-to-transfect Jurkat T and CEM T cells. We have also demonstrated that NH4+ can synergistically interact with arsenic trioxide (arsenite) to further promote ON function without producing any apparent increased cellular toxicity. These small, inexpensive, widely distributed molecules could be useful not only in laboratory experiments but potentially in therapeutic ON-based combinatorial strategy for clinical

Silenseed- Targeted Therapies for Prostate Cancer-

Prostate cancer is a cancer that starts in the prostate gland. It is the third most common cause of death from cancer in men of all ages and is the most common cause of death from cancer in men over the age of 75. Prostate cancer is rarely found in men younger than 40. More than 1.1 million cases of prostate cancer were recorded in 2012 worldwide, accounting for approximately 8 percent of all new cancer cases and 15 percent in men. In 2018, the American Cancer Society predicts that there will be around 164,690 new diagnoses of prostate cancer, and that around 29,430 fatalities will occur because of it in the United States.
Prostate cancer is a cancer that starts in the prostate gland. It is the third most common cause of death from cancer in men of all ages and is the most common cause of death from cancer in men over the age of 75. Prostate cancer is rarely found in men younger than 40. More than 1.1 million cases of prostate cancer were recorded in 2012 worldwide, accounting for approximately 8 percent of all new cancer cases and 15 percent in men. In 2018, the American Cancer Society predicts that there will be around 164,690 new diagnoses of prostate cancer, and that around 29,430 fatalities will occur because of it in the United States. Treatment is different for early and advanced prostate cancers. In early stage prostate cancer, If the cancer is small and localized, it is usually managed by one of the following treatments: Watchful waiting or monitoring, based on PSA blood levels; Radical prostatectomy where the prostate is surgically removed; Brachytherapy using radioactive seeds that are implanted into the prostate to deliver targeted radiation treatment; Conformal radiation therapy; and Intensity modulated radiation therapy. Patients may receive radiation therapy combined with hormone therapy for 4 to 6 months.

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Mutant KRAS is a druggable target for pancreatic cancer

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) represents an unmet therapeutic challenge. PDA is addicted to the activity of the mutated KRAS oncogene which is considered so far an undruggable therapeutic target. We propose an approach to target KRAS effectively in patients using RNA interference. To meet this challenge, we have developed a local prolonged siRNA delivery system (Local Drug EluteR, LODER) shedding siRNA against the mutated KRAS (KRAS-LODER). The KRAS-LODER was assessed for its structural, release, and delivery properties in vitro and in vivo. The effect of the KRAS-LODER on tumor growth was assessed in s.c. and orthotopic mouse models. KRAS silencing effect was further assessed on the KRAS downstream signaling pathway. The LODER-encapsulated siRNA was stable and active in vivo for 155 d. Treatment of PDA cells with KRAS-LODER resulted in a significant decrease in KRAS levels, leading to inhibition of proliferation and epithelial–mesenchymal transition. In vivo, KRAS-LODER impeded the growth of human pancreatic tumor cells and prolonged mouse survival. We report a reproducible and safe delivery platform based on a miniature biodegradable polymeric matrix, for the controlled and prolonged delivery of siRNA. This technology provides the following advantages: (i) siRNA is protected from degradation; (ii) the siRNA is slowly released locally within the tumor for prolonged periods; and (iii) the KRAS-LODER elicits a therapeutic effect, thereby demonstrating that mutated KRAS is indeed a druggable target.

2013 Zorde Khvalevsky Silenseed pre-clinical PNAS

Talia Golan, Elina Zorde Khvalevsky, Ayala Hubert, Rachel Malka Gabai, Naama Hen, Amiel Segal, Abraham Domb, Gil Harari, Eliel Ben David, Stephen Raskin, Yuri Goldes, Eran Goldin, Rami Eliakim, Maor Lahav, Yael Kopleman, Alain Dancour, Amotz Shemi and Eithan Galun, Oncotarget May 19, 2015


Purpose: The miniature biodegradable implant KRAS-LODER™ was inserted into a tumor and released a siRNA drug against KRAS(G12D) along four months. This novel siRNA based drug was studied, in combination with chemotherapy, as targeted therapy for Locally Advanced Pancreatic Cancer (LAPC).

Methods: An open-label Phase 1/2a study in the first-line setting of patients with non-operable LAPC was initiated. In this study patients were assigned to receive a single dose of KRAS-LODERs, in three escalating dose cohorts (0.025mg, 0.75mg and 3.0mg). Gemcitabine was given on a weekly basis, following the siG12D-LODERTM insertion, until disease progression. The recommended dose was further examined with modified FOLFIRINOX. The follow up period was eight weeks and survival until death.

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Ramot Y, Rotkopf S, Gabai RM, Khvalevsky EZ, Muravnik S, Marzoli GA, Domb AJ, Shemi A, Nyska A.

Abstract: Conventional chemotherapy treatments for pancreatic cancer are mainly palliative. RNA interference (RNAi)-based drugs present the potential for a new targeted treatment. LOcal Drug EluteR (LODERTM) is a novel biodegradable polymeric matrix that shields drugs against enzymatic degradation and releases small interfering RNA (siRNA) against G12D-mutated KRAS (siG12D). KRAS-LODER has successfully passed a phase 1/2a clinical trial. Such a formulation necessitates biocompatibility and safety studies. We describe the safety and toxicity studies with KRAS-LODER in 192 Hsd:Sprague Dawley rats, after repeated subcutaneous administrations (days 1, 14, and 28). Animals were sacrificed on days 29 and 42 (recovery phase). In all groups, no adverse effects were noted, and all animals showed favorable local and systemic tolerability. Histopathologically, LODER implantation resulted in the expected capsule formation, composed of a thin fibrotic tissue. On the interface between the cavity and the capsule, a single layer composed of macrophages and multinucleated giant cells was observed. No difference was noted between the placebo and KRAS-LODER groups. These findings provide valuable information for future preclinical studies with siRNA-bearing biodegradable polymers and for the safety aspects of RNAi-based drugs as a targeted therapy.

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Amotz Shemi, Elina Zorde Khvalevsky, Rachel Malka Gabai, Abraham Domb, Yechezkel Barenholz, Oncotarget , Sep 22, 2015

Abstract: The distribution of drugs within solid tumors presents a long-standing barrier for efficient cancer therapies. Tumors are highly resistant to diffusion, and the lack of blood and lymphatic flows suppresses convection. Prolonged, continuous intratumoral drug delivery from a miniature drug source offers an alternative to both systemic delivery and intratumoral injection. Presented here is a model of drug distribution from such a source, in a multistep process. At delivery onset the drug mainly affects the closest surroundings. Such ‘priming’ enables drug penetration to successive cell layers. Tumor ‘void volume’ (volume not occupied by cells) increases, facilitating lymphatic perfusion. The drug is then transported by hydraulic convection downstream along interstitial fluid pressure (IFP) gradients, away from the tumor core. After a week tumor cell death occurs throughout the entire tumor and IFP gradients are flattened. Then, the drug is transported mainly by ‘mixing’, powered by physiological bulk body movements. Steady state is achieved and the drug covers the entire tumor over several months. Supporting measurements are provided from the LODER™ system, releasing siRNA against mutated KRAS over months in pancreatic cancer in-vivo models. LODER™ was also successfully employed in a recent Phase 1/2 clinical trial with pancreatic cancer patients.

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Richard A. Stein. Genetic Engineering & Biotechnology News. 2017.
An advantage of the LODER platform is that it delivers RNAi locally, within the tumor, Circumventing systemic toxicity and the need for large systemically administered doses.
“We have preclinical and clinical data showing that our treatment is safe,” asserts Dr. Shemi. “It affects the development of tumors and impedes the development of new metastases.”

Unpublished preclinical studies show that Loder may be used in combination with immune-oncology treatments. “We strongly believe that this combination can open new markets for many companies for treating pancreatic cancer and possibly other solid tumors,” comments Dr. Shemi.

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Ricardo Titze-de-Almeida, Catherine David & Simoneide Souza Titze-de-Almeida. Pharmaceutical Research. 2017.

“KRAS-LODER made KRAS a druggable anticancer target. New drugs also targeting this oncogene are now in test and may represent future competitors of KRAS-LODER. KRAS-LODER is the only RNAi-based drug that provides a sustained release of siRNA into the tumor region thanks to a well-known biodegradable PLGA polymer, approved by FDA for drug delivery.
This siRNA represents a hopeful strategy against advanced pancreatic cancer…. Taking the aggressive behavior of pancreatic tumor cells, KRAS-LODER is a promising anticancer therapy.
Results of a phase 1/2a was positive in a relatively small number of patients, so we must wait for an ongoing phase 2 study that is testing KRAS-LODER (2.8 mg) plus standard chemotherapy for patients with unresectable advanced pancreatic cancer”

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Benjamin A. Krantz, Kenneth H. Yu, Eileen M. O’Reilly.

Chinese Clinical Oncology. 2017.

“Targeting RAS by inhibiting
translation using small-interfering RNAs is a novel strategy
to decrease RAS activity. siRNA against the G12D mutant
RAS RNA by local prolonged delivery, KRAS-LODER
(Local Drug EluteR), has demonstrated decreased growth of
human pancreatic tumor cells in vivo and prolonged mouse
survival. In a phase Ib/II dose escalation 15 locally
advanced, unresectable patients received KRAS-LODER
with a mOS of 15.12 months. Ten out of 12 patients
had SD on repeat imaging and 2 had a PR.”

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Silenseed Phase II pancreatic cancer drug -Amotz Shemi

Israeli drug development company Silenseed is to begin a Phase II multicenter trial for its pancreatic cancer treatment. The study, which has been approved by the US Food and Drug Administration (FDA), will be held at several leading medical centers in the US with the participation of 80 patients. At the same time, the Modi’in based company is raising $10 million in order to help conduct the trial. To date, Silenseed has raised $10 million, mainly from private investors, including leading Israeli cancer researchers.

Silenseed’s drug is based on siRNA, a promising technology which has yet to be translated into an effective treatment. siRNA has been marked out as a potential new family of drugs compared with most treatments today which are based on proteins or protein agents. siRNA prevents the decoding of certain proteins from a gene called KRAS, which creates a mutation that becomes a cancerous cell.

the slow progress made by siRNA technology stems among other things through the difficulty of delivering the RNA to the right place in the body and into the cell because it breaks up so easily.

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