The Metastatic Pancreatic Adenocarcinoma Project


To Enhance the Clinical Response and Clinical Outcomes of an FDA-Approved Treatment for Metastatic Pancreatic Adenocarcinoma

The Unresolved Problems:

Despite important advancements in cancer treatments in the last half century, continued limitations in the therapeutic potential of most drugs for the treatment of different cancers are due to their non-specific targeting with resultant unacceptably high systemic toxicities, inadequate treatment results, and rapid development of drug resistance.

Metastatic pancreatic adenocarcinoma is a catastrophic disease for which all current treatments increase life expectancy by only 6 to 8 months on average from the time of diagnosis. The 5-year survival rate is approximately only 6%, and mortality closely reflects its incidence. Unfortunately, it is a silent disease, growing slowly for years before symptoms arise, which is only after metastases have occurred.

While surgical resection is considered the only curative therapy, it is helpful only to those few people diagnosed in the very early stage of disease, before metastases have occurred.

Until recently, the chemotherapeutic agent Gemcitabine (Gemzar/Eli Lilly) had been the only antiproliferative that provided a modicum of benefit for pancreatic adenocarcinoma and was the standard of care for 15 years.

In 2013, the combination of non-targeted gemcitabine and non-targeted nab-paclitaxel, both widely used anti-neoplastic agents for a variety of cancers, was approved by the FDA as a first-line treatment for metastatic pancreatic carcinoma after analysis of a three year multi-center study of 861 patients comparing the combination of the two drugs against gemcitabine alone. The results of this study showed that patients who had received gemcitabine alone achieved an overall survival of 6.7 months on average, while those receiving a synergistic proapoptotic activity of each compound given in combination survived on average for 8.5 months.

Although the combination of treatments resulted in a small but statistically significant improvement in overall survival rate of 1.8 months, there remains an urgent need to develop better approaches to the treatment of pancreatic cancer and improve these results.


CLR-TargoSphere®- encapsulated gemcitabine, paclitaxel, and curcumin targeted to Antigen-presenting Cells for delivery to tumor cells and enhancement of anti-tumor antibody and cytokine activity:

  1. Gemcitabine antiproliferative activities:Gemcitabine (Gemzar/Eli Lilly) is an agent whose pro-apoptotic action differs from, but synergizes with paclitaxel. Gemcitabine is a nucleoside analog deoxycytidine antimetabolite, and is one of the most widely used anticancer drugs. It is approved for the treatment of many types of solid tumors, including metastatic pancreatic cancer, non-small cell lung cancer, breast cancer, head and neck squamous cell carcinoma, cervical, bladder, colon, ovarian, and thyroid cancers.It was originally synthesized in the laboratories of Eli Lilly in the 1980s as an antiviral drug. Preclinical testing indicated that it killed leukemia cells in-vitro. It was licensed in 1995 and became the first line of treatment for bladder cancer Stage 4 with metastases, in combination with cisplatin. It was also more recently found to have a modest effect on advanced cancer of the biliary tract and gallbladder when combined with cisplatin. Gemcitabine is also used in combination with carboplatin to treat cancer of the lung. Its mechanism of action, as with other analogues of pyrimidines, is to interfere with DNA replication, as well as to inactivate the enzyme ribonucleotide reductase (RNR). Both processes result in inhibition of DNA replication, inducing cancer cell apoptosis and arrest of tumor growth.

    Factors limiting its efficacy, however, are its rapid inactivation following intravenous administration and the early development of tumor resistance resulting in short remissions with recrudescence of aggressive growth of the tumor and metastases. Tumor resistance is attributed to multiple factors (13): Over-expression of cytidine deaminase and a deficiency of deoxycytidine kinase and deregulation of p53 (14); and loss of CNT1 expression (15).

    Also, due to its complex pharmacodynamics profile, the antitumor effects of gemcitabine are more dependent on the frequency of administration than dosage, and a suitable therapeutic response can only be obtained following daily administration or prolonged infusion for some cancers. These issues are not isolated to the use of gemcitabine, but to other antiproliferative drugs as well, such as doxorubicin. Consequently, different strategies have been developed to overcome these problems (16).

    Gemcitabine-loaded PEGylated liposomes studied in-vivo protected gemcitabine from enzymatic degradation with improved accumulation in tumor tissues due to increased vascular permeability. Encapsulation increased the half-life of gemcitabine and enhanced its antitumor activity (17).

    Additionally, a multidrug liposomal carrierencapsulating both gemcitabine and paclitaxel has been successfully developed to obtain a synergistic therapeutic effect based on the fact that each compound induces apoptosis by different mechanisms. (18, 19).

    A nanoparticle drug delivery combining gemcitabine with curcumin has been shown to retard tumor growth, abolish systemic metastases, reduce activation of NF-kB, and reduce expression of matrix metalloproteinase-9 and cyclin D1 in a pancreatic xenograft model, as compared to either drug alone (20).

    Of all the nanodelivery strategies developed, liposome encapsulation has been consistently approved by the FDA for the treatment of cancer. It has been well demonstrated that the use of liposomes for the treatment of solid tumors protects the encapsulated drug from rapid inactivation following parenteral administration and reduces toxicity to healthy tissues before it reaches its site of action (21,22).

  2. Paclitaxel Antiproliferative and Immune-Enhancing Activities:Paclitaxel is a chemotherapeutic agent whose action as a microtubule stabilizer interferes with the normal breakdown of intracellular microtubules during cell division, resulting in apoptosis (cell death) of the cancer cell. Importantly, as with other pro-apoptotic agents, it has been shown to act indirectly upon the immune system to enhance the presence and number of tumoricidal macrophages at the tumor sites, thereby reducing cancer invasion, angiogenesis, and metastasis by its influence upon anti-tumor cytokines and growth factors (1, 2). Paclitaxel is among the third highest prescribed chemotherapy agents globally, approved for many cancers including Kaposi’s sarcoma, non-small cell lung cancer, breast, and ovarian cancer.

    Despite formulations which attempt to target the tumor and avoid systemic circulation, it continues to be associated with therapeutic failures due to the development of tumor resistance and the continued incidence of serious systemic toxicities to bone marrow and normal cell populations. From a clinical perspective, the original formulation of paclitaxel dissolved in Cremophor (an excipient now termed Kolliphor, a version of polyethoxylated castor oil) is associated with severe toxic and hypersensitive reactions. Cremophor was required to solubilize the drug for intravenous administration. Consequently, many approaches have been developed to administer it systemically to avoid this toxic effect.

    One such development of an alternative formulation, is albumin-bound paclitaxel, nab-paclitaxel (Abraxane/Celgene), in which paclitaxel is bound to albumin as an alternative, non-specific delivery agent. It was approved by the FDA in 2005.

    Other formulations have been developed with fewer side effects and improved uptake by cancer cells. These include: DHA paclitaxel (Protarga) in which a fatty acid easily taken up by tumor cells is linked to paclitaxel; PG-paclitaxel (Cell Therapeutics) in which paclitaxel is bonded to a polyglutamate polymer to be more easily taken up by cancer cells; and continued early development of tumor-activated payload (TAP) technology (Novartis and ImmunoGen) in which accurate tumor targeting is achieved by the action of a monoclonal antibody specific to different tumor cells.

    Paclitaxel remains the third highest prescribed chemotherapy agents globally, approved for many cancers including Kaposi’s sarcoma, non-small cell lung cancer, breast, and ovarian cancer. However, despite all formulations which attempt to target the tumor and avoid systemic circulation, it continues to be associated with therapeutic failures due to the development of tumor resistance and the continued incidence of serious systemic toxicities to bone marrow and normal cell populations.

    The CLR-TargoSphere® with encapsulated Paclitaxel is the first apoptotic agent having dual antiproliferative and immune-enhancing functions to be successfully targeted to the APCs.

    It is designed specifically to target APCs, including the myeloid Dendritic Cells and the DC-instructed Cytotoxic T Lymphocytes. In addition to targeting the primary tumor and metastases, the CLR-TargoSphere® will also deliver its paclitaxel payload to the Tumor-Associated Macrophages (TAM type-1 and TAM type-2) which act either as tumor-inhibiting (M1) or tumor-promoting (M2) immune cells in the tumor nests and stroma.

    We have demonstrated that the CLR-TargoSphere® has a preferential affinity for M2 macrophages. Paclitaxel is known to influence the enhancement and anti-tumor activity of M1 tumoricidal macrophages. Therefore, delivering paclitaxel preferentially to type-2 TAMs may inhibit the development of M2 (tumorigenic) macrophages.

  3. Curcumin Antiproliferative and Anti-inflammatory Properties:Curcumin, a diferuloylmethane, is a phytochemical derived from the rhizome of Curcuma longa, a member of the ginger family. It has been used orally for at least 2,500 years in southern Asia and India. There are numerous published articles on in-vitro and in-vivo animal and human studies examining its effect as an anti-proliferative and anti-inflammatory on a wide variety of diseases. Despite results of some studies showing lack of in-vivo efficacy due to poor oral bioavailability, the majority of research over the last several decades has shown striking results with curcumin in a number of different diseases, and particularly a number of different cancers.

Significant literature on the anti-inflammatory and synergistic antiproliferative properties of curcumin:

  • It enhances induction of tumor antigen-specific, PD-1-positive CTLs. Delivering curcumin to activated T cells has been shown to enhance induction of tumor antigen-specific PD-1 positive CTLs (23,24);
  • It arrests cancer cells in various phases of the cell cycle, and induces apoptosis primarily through a mitochondrial pathway involving caspase-8-dependent BID cleavage (25);
  • It has been shown to inhibit constitutive NF-kB activation, induce G1/S arrest, suppress proliferation, and induce apoptosis in mantle cell lymphoma (26);
  • It inducesapoptosis in human melanoma cells  through a Fas Receptor/Caspase-8 pathway independent of p53 (27);
  • It suppresses the proliferation of human vascular endothelial cells in vitro and inhibits the Fibroblast Growth Factor-2-induced angiogenic response in-vivo (28);
  • It induces apoptosis in the human acute myelogenous leukemia cell line HL-60, believed to occur through the mitochondrial pathway involving caspase-8, BID cleavage, cytochrome C release, and caspase-3 activation (29);
  • It downregulates action of NF-kB and the antiapoptotic genes regulated by NF-kB, a critical role in inhibiting cancer cell survival and proliferation in pancreatic cancer (30, 31);
  • It suppresses expression of NF-kB, Bcl-2 and Bcl-XL in multiple myeloma cell lines (31);
  • A liposomal-encased formulation of curcumin was studied in pancreatic cancer cell lines in vitro and in vivo, by intravenous infusion, in athymic mice at the M.D. Anderson Cancer Center in Houston, Texas. Liposomal Curcumin was shown to down-regulate the NF-kB machinery, suppress tumor growth, and induce apoptosis in vitro, and demonstrated a reduction in tumor burden and angiogenesis in vivo (32);
  • It potentiates the antitumor activity of gemcitabine in an in-vivo pancreatic cancer model through suppression of proliferation, angiogenesis, and inhibition of NF-kB -regulated gene products (33);
  • It induces gemcitabine sensitivity in pancreatic cancer cellsthrough modulation of miR-200 and miR-21 expression (34);
  • It inhibits tumor growth and angiogenesis in an orthotopic mouse modelof human pancreatic cancer (35);
  • It induces apoptosis in squamous cell carcinoma head and neck cell lineswith suppression of NF-kB, cell proliferative genes including Bcl-2, cyclin D1, IL-6, COX -2, and MMP-9 (36);
  • A nanoparticle non-targeted drug delivery combining gemcitabine with curcumin has been shown to retard tumor growth, abolish systemic metastases, reduce activation of NF-kB, and reduce expression of matrix metalloproteinase-9 and cyclin D1 in a pancreatic xenograft model, as compared to either drug alone (37).


Targeting metastatic pancreatic carcinoma primary tumor and metastases in a pancreatic tumor xenograft mouse model with the concomitant administration of CLR-TargoSphere® encapsulated gemcitabine, paclitaxel, and curcumin.

Our treatment strategy for pancreatic adenocarcinoma is to target the myeloid DCs and circulating monocytes as well as TAMs with CLR-TargoSphere®-encapsulated gemcitabine, paclitaxel, and curcumin to be delivered to the primary tumor nests, stroma, and metastatic lesions in pancreatic adenocarcinoma, to inhibit tumor angiogenesis, tumor growth, and tumor migration.


Administer CLR-TargoSphere® encapsulated gemcitabine, paclitaxel, and curcumin separately, and in alternating dosages for prolonged administration, with lowered daily total therapeutic dosaging, decreased systemic distribution, decreased systemic toxicities, decreased development of drug resistance, with increased treatment response and overall survival rate.



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