Fenretinide Applications in Cancer Combination Therapy
A Brief Overview
Louis M. Scarmoutzos, Ph.D.
Combination therapy is a medical treatment that combines two or more therapies to treat a single disease. Usually, the combined therapies are two or more pharmaceuticals or drugs although it can also involve non-pharmaceuticals such as any combination of drugs, devices, surgery, and radiation.
Combination therapy has become a cornerstone in cancer treatment. The stage and type of cancer often dictates whether single therapy (monotherapy) or combination therapy is necessary or warranted. The practice of combination therapy has been particularly useful with aggressive and metastatic cancers as well as in reducing drug resistance. 
Combination therapy does have its disadvantages. More medications generally mean a greater risk of side effects. The combination of two or more drugs may additively or synergistically create unwanted side-effects or toxicities. Side effects may also occur as a result of reactions between the drugs or their metabolites.
Cancer immunotherapy treatments such as immune checkpoint blockers (ICBs), adoptive cell therapy (ACT), monoclonal antibodies (mAb), immune system modulators (immune-modulating agents), and treatment vaccines have enjoyed great success in recent years and have changed the cancer treatment landscape.
However, increasing use of immunotherapy cancer treatments continues to reveal several significant shortcomings, notwithstanding their significant costs; notably, their effectiveness in limited patient populations, fluctuation of patient response rates, and overactive patient immune systems to name a few. In addressing these limitations, scientists have increasingly turned to combination therapy, an approach that reflects cancer's characteristic heterogeneity and dynamic nature. In fact, the FDA has recently approved several chemotherapy and immunotherapy combinations. 
Fenretinide's unique multiple mechanisms of action make it an ideal candidate for use in combination therapy . In cancer combination treatment, the selection of two or more co-therapeutic drugs requires careful consideration of the toxicities associated with each of the agents. Ideally, the toxicities of each of the selected co-therapeutics should be minimal and not overlap. Additional considerations include the stage and type of cancer, the nature of the cancer (aggressive, metastatic) and the need to reduce drug resistance.
Fenretinide (4-hydroxyphenylretinamide or 4-HPR) is the active pharmaceutical ingredient (API) in SciTech's lead cancer drug candidate ST-001 nanoFenretinide. ST-001 is a phospholipid nanoparticle formulation that enhances the bioavailability of fenretinide. Fenretinide is a drug with a well-documented safety profile  which has shown promise in a number of drug combination studies as briefly highlighted below.
A review of the the history of fenretinide, its properties, and use as an experimental cancer treatment (monotherapy) in clinical studies has been described elsewhere (www.SciTechDevelopment.com/fenretinide).
Fenretinide appears promising as both a monotherapy and a combination therapy for the treatment of several types of cancer. Fenretinide has not yet gained FDA approval and continues to remain an experimental drug or treatment. Fenretinide’s lack of commercialization is most likely due to its limited bioavailability and patentability. These obstacles have been recently addressed and overcome by SciTech Development and others.
Efforts directed towards enhancing fenretinide's bioavailability include the use of several approaches and drug delivery systems (DDS) including lipid emulsions , cyclodextrins , liposomes [7,8], polymeric micelles , ion-pair stabilized lipid matrix , gelatin matrix , lym-x-sorb (LXS) lipid matrix , fenretinide-PEG (polyethylene glycol) conjugates , and SciTech Development’s SDP drug delivery platform .
Given below are fenretinide drug combinations reported for several select preclinical and clinical cancer studies. Also given below is a table which lists fenretinide combination studies currently registered on the ClinicalTrials.gov website. These registered clinical studies include fenretinide combined with bexarotene, cisplatin, cytarabine, ketoconazole, methotrexate, paclitaxel, rituximab, safingol, tamoxifen, tretinoin (retinoic acid), vincristine, and surgery.
Fenretinide drug combination therapy has been used as an experimental treatment in several pediatric or childhood cancer indications including the treatment of alveolar rhabdomyosarcoma (aRMS), diffuse intrinsic pontine glioma (DIPG), Ewing's sarcoma, neuroblastoma, and rhabdoid tumors.
Fenretinide Drug Combinations in Preclinical Studies
Several preclinical studies have been reported for fenretinide drug combinations and include lenalidomide (Revlimid®) and fenretinide for the treatment of neuroblastoma ; bortezomib (Velcade®) and fenretinide for the treatment of metastatic melanoma ; selenite (Na₂SeO₃) and fenretinide for the treatment of ovarian cancer ; and ABT-263 (Navitoclax) and fenretinide for the treatment of head and neck squamous cell carcinoma (HNSCC) .
Kocdor et al  report that rosiglitazone (Avandia®) and fenretinide have potent chemopreventive properties against in vivo mammary carcinogenesis in their preclinical rat mammary carcinogenesis model; however, the efficacies were not enhanced by their combination.
Orienti et al evaluated a novel class of antitumor amphiphilic amines that can also function as nanocarriers for bioactive molecules . Utilizing this approach, the authors found that the combination of fenretinide with a quaternary amphiphilic amine RC16+ generated fenretinide-RC16+ complexes with improved fenretinide aqueous solubility as well as strong antitumor activity in neuroblastoma cell lines and related xenografts . The authors state that the fenretinide-RC16+ complex provides a multitasking system for antitumor therapy.
Hojka-Osinska et al  report that the combination of fenretinide and the non-steroidal anti-inflammatory drug (NSAID) indomethacin (also known as indometacin, indocid, indocin and Tivorbex®) induces a high level of cell death in the acute human T-cell leukemia cell line Jurkat. The authors detailed observations include cell membrane permeabilization, phosphatidylserine exposure, no oligonucleosomal DNA fragmentation, no caspase-3 activation, but apoptosis inducing factor (AIF) nuclear translocation. Taken together, the authors state that their results indicate that Jurkat cells undergo AIF-mediated programmed cell death.
Cuperus et al report  that the combination of fenretinide and buthionine sulfoximine (BSO), an inhibitor of glutathione synthesis, may be a promising strategy for the treatment of neuroblastoma. The authors report that the combination increased cytotoxicity compared to fenretinide treatment alone, presumably via induced reactive oxygen species (ROS).
Preclinical studies that combined fenretinide and radiation suggests that this combination therapy may be a potent treatment for the pediatric cancer indications fusion-positive rhabdomyosarcoma (FP-RMS)  and diffuse intrinsic pontine glioma (DIPG) . The authors of the FP-RMS preclinical fenretinide-radiation combination study further report that fenretinide acts as a potent radiosensitizer.
In metastatic melanoma preclinical studies, Hill et al  demonstrated that the combination of fenretinide and bortezomib (Velcade®) synergistically decreased viability and increased apoptosis in their model human melanoma cell lines. The authors state their results warrant clinical evaluation as a combination therapy for metastatic melanoma.
In a preclinical study of ovarian cancer, Liu et al report  the combination of fenretinide and selenite (Na₂SeO₃) had an enhanced anti-tumor effect on ovarian cancer cells. The drug combination suppressed tumor growth of ovarian cancer cells and induced apoptosis (including reactive oxygen species generation and the loss of mitochondrial membrane potential) compared with either drug used alone.
Preclinical studies conducted by Formelli et al  show that fenretinide combined with all-trans retinoic acid (RA or ATRA) and cisplatin [PtCl2(NH3)2] may be an effective treatment for ovarian tumors. Their findings demonstrated that fenretinide may enhance cisplatin sensitivity in cisplatin-sensitive and cisplatin-resistant ovarian tumors. The authors further conclude that the association of RA and fenretinide may result in increased fenretinide antitumor activity.
Several other preclinical studies have reported an enhanced or synergistic effect including fenretinide combined with the histone deacetylase inhibitors (HDACi) romidepsin (Istodax®)  and vorinostat (Zolinza®)  for the treatment of T-cell lymphoid malignancies; the BCL-2 inhibitors venetoclax (Venclexta®)  and ABT-737 [20, 21] for the treatment of neuroblastoma and acute lymphoblastic leukemia (ALL); CD20-directed cytolytic antibodies (rituximab or Rituxan®)  for the treatment of B-cell lymphoma; and the natural product indole-3-carbinol  for the treatment of breast cancer.
Additional synergistic effects have been reported in preclinical studies of fenretinide and curcumin for the treatment of non-small cell lung cancer (NSCLC) ; fenretinide and etoposide for treatment of small cell lung cancer (SCLC) ; fenretinide and paclitaxel for treatment of small cell lung cancer (SCLC) ; fenretinide and cisplatin for treatment of small cell lung cancer (SCLC) ; fenretinide and bortezomib (Velcade®) for treatment of mantle cell lymphoma (MCL)  and neuroblastoma .
In the small cell lung cancer (SCLC) study, Kalemkerian et al  report that combinations of fenretinide with cisplatin, etoposide or paclitaxel inhibited growth in their model small cell lung cancer (SCLC) cell lines. The authors further state that activities of the fenretinide combinations were more than additive and the combinations may be promising investigational regimens for the treatment of patients with SCLC.
Preclinical studies in a human head and neck squamous cell carcinoma (HNSCC) cell line and mouse squamous cell carcinoma tumors suggests that the combination of fenretinide and photodynamic therapy (PDT) may be an effective cancer treatment for squamous cell carcinoma (SCC). The authors of the study report that the combination of fenretinide and PDT enhanced apoptotic cancer cell killing and antitumor efficacy and the combination is a more effective anticancer treatment than either treatment alone .
Synergistic fenretinide drug combinations have also been reported in several preclinical pediatric or childhood cancer studies and include combinations of fenretinide with the antimitotic sulfonamide ABT-751 , the histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA or vorinostat) and the anthracycline doxorubicin (also known as Adriamycin®, Rubex®; and, as Doxil® in liposomal formulations) , the ceramide modulator safingol (l-threo-dihydrosphingosine)  and radiation [31, 32].
In their study of inducing apoptosis of cancer cells using small-molecule plant compounds that bind to glucose regulated protein 78 (GRP78), a sensor of endoplasmic reticulum (ER) stress, Martin et al  found that the combination of honokiol and fenretinide displayed synergistic effects on melanoma and glioblastoma cells but only additive effects on neuroblastoma cells.
Xiaopeng Mo et al  report that the combination of fenretinide and simvastatin (Zocor®) was potent for treating glioma. The drug combination was encapsulated into lactoferrin nanoparticle systems for brain-targeted drug delivery. The authors state that this drug delivery and therapeutic strategy provides a novel modality for glioma treatment.
Lovat et al , found that pre-treatment of neuroblastoma cell lines with fenretinide prior to treatment with cisplatin, etoposide or carboplatin synergistically increased apoptosis. Quenching of fenretinide-induced free radicals with antioxidants eliminated the synergistic response seen upon subsequent addition of chemotherapeutic agents, suggesting that the free radicals may be the key property of leading to synergistic responses with chemotherapeutic drugs.
Park et al  report that apoptosis induced by fenretinide could be effectively enhanced in hepatoma cells by a concomitant treatment with parthenolide (naturally occurring sesquiterpene lactone), a known inhibitor of nuclear factor-κB (NF-κB).
Kim et al  report that tetrathiomolybdate (TM or (NH4)2MoS4), a copper chelator, combined with fenretinide (as well as TM combinations with mitomycin C, 5-fluorouracil and doxorubicin) can sensitize drug-resistant endometrial cancer cells to these anticancer drugs in a ROS-dependent manner. The authors suggest that the combination of fenretinide and TM may be considered in the treatment of ovarian or other cancers and the use of tetrathiomolybdate (or its derivatives) in combination therapy may improve cancer treatment options.
An international patent filing claims combination compositions for treating hyperproliferative disorders; notably, inhibiting or slowing tumor or cancerous growth . Preferred compositions include fenretinide combined with one or more of the following: L-threo-sphinganines, glucosylceramide or glucosyl(dihydro)ceramide synthesis inhibitor(s) and sphingomyelin or dihydrosphingomyelin synthase inhibitor(s). A preferred hyperproliferative disorder is brain cancers. Interestingly, the patent was abandoned in the United States.
It is noteworthy to mention that a recently issued patent makes claim of a cancer combination therapy comprised of oncolytic herpes simplex virus (HSV) and pharmaceutical compositions, including fenretinide, for the treatment of certain hematologic and solid tumors .
Finally, it is well worth mentioning that the combination of fenretinide and 3-keto-HPR (4-oxo-fenretinide), a fenretinide metabolite, has been reported to kill cancer cells more effectively than fenretinide, inhibit fenretinide-resistant cell growth, and act synergistically in combination with fenretinide [33, 34].
Tiberio et al report that unlike fenretinide [51, 52], 4-oxo-fenretinide inhibits tubulin polymerization in their A2780 human ovarian cancer cell line independent of oxidative stress (ROS). This addditional unique mechanism of action (mitotic arrest) may provide an explanation for 4-oxo-fenretinide's enhanced potency compared to fenretinide as well as its effectiveness in fenretinide-resistant cell lines. The combination of fenretinide and 4-oxo-fenretinide exerted a synergistic effect that may also act to counteract the development of drug resistance.
Clinical Studies of Fenretinide Drug Combination Regimens
Only the results of a limited number of clinical studies have been reported for fenretinide combination therapies. Cowan et al , in a phase I-II study of fenretinide and rituximab (Rituxan®) for patients with indolent B-cell lymphoma and mantle cell lymphoma reported that the combination was well-tolerated, yielded a modest overall response rate, but with prolonged remission durations. The authors suggest further studies should focus on identifying the responsive subset of B-cell non-Hodgkin lymphoma (B-NHL).
Otterson et al  reported that the combination of fenretinide, paclitaxel (Taxol®), and cisplatin for refractory solid tumors can be administered safely at 1800/135/60 (mg/m2), respectively. The authors report that this combination may have activity in a variety of tumors; however, the number of pills required complicates the oral dosing of fenretinide and limits the applicability of this drug combination regimen.
Decensi et al  reported a two-year study of the combination of low-dose tamoxifen plus fenretinide showed that both agents were safe; however, the combination did not reduce breast neoplastic events compared to placebo. Both single agents, particularly fenretinide, showed a numerical reduction in annual odds of breast neoplasms and additional follow-up is warranted.
Chiesa et al  assessed the efficacy of fenretinide at preventing relapses, new lesions and carcinomas after surgical excision of oral leukoplakia in a controlled multicenter study. The authors of the study found that fenretinide was well tolerated and effective at preventing relapses and new leukoplakias during treatment and up to 19 months after treatment. The trial was stopped prematurely due to low patient recruitment and insufficient power to reveal any long-term protective effect against oral carcinoma. The authors suggest continuing studies are justified.
Given in the table below are fenretinide drug combination studies currently registered on ClinicalTrials.gov with no results reported, to date (September 20, 2022). These registered clinical studies include fenretinide as a co-therapeutic with a number of different agents and surgery.
Fenretinide has shown promising anticancer activity as a combination therapy in many preclinical studies and several clinical studies. Fenretinide’s well-documented safety profile makes it eminently suitable as a co-therapeutic in cancer combination therapy.
It is tempting to suggest that the limited therapeutic outcomes reported in the fenretinide combination clinical studies may be due to the limited bioavailability associated with the orally administered fenretinide. Considering fenretinide's safety profile and affordability, it would be particularly beneficial to re-evaluate fenretinide combination therapies with the enhanced bioavailable forms of fenretinide currently available.
The evaluation of enhanced bioavailable fenretinide formulations as a co-therapeutic may be particularly useful and beneficial in the application of cancer immunotherapy treatments. Fenretinide could provide a safe, affordable, co-therapeutic which may ameliorate the limitations currently associated with these new cancer treatment modalities.
Recent studies suggest that this combination of immunotherapy and chemotherapy may be a promising direction for the treatment of several types of cancer. For example, initial clinical results of cytotoxic or chemotherapeutic agents combined with immunotherapies have been shown to be promising in the treatment of non-small cell lung cancer (NSCLC) and pancreatic cancer . Combining immunotherapy with other treatments is showing great promise against a variety of cancers with many clinical trials currently underway in the United States .
Key practical considerations in the administration of combination therapy include timeliness and function. Does one employ the drugs or therapies simultaneously or administer one before and then the other(s) after? If so, how long of a wait time? These questions may be paramount when combining one therapy such as a drug with radiation or surgery.
Additional considerations include whether one therapy will be selected to function in one manner and the other(s) selected and targeted to function differently. For example, will one of the selected therapies be a highly targeted immunotherapy and the other a more general anti-cancer agent or adjuvant therapy, which may be the case with fenretinide and other chemotherapeutic agents.
The present article has provided a brief overview of cancer therapy combinations, specifically with a focus on fenretinide combination therapy. It is immediately obvious that the number of ways in which one therapy may be combined with others is immense. Determining which combinations work best for patients will take considerable time, money and hundreds, if not thousands of clinical trials.
Large pharmaceutical companies have been reluctant to further fenretinide's drug development as a treatment for cancer. This may be due to fenretinide's past history of clinical shortcomings (and associated negative connotations) as well as limitations in its patentability. Fenretinide itself has long since come off-patent.
Several novel fenretinide formulations now exist that successfully address the oral bioavailability limitations of fenretinide, including SciTech Development’s patented, lead cancer drug candidate ST-001 nanoFenretinide . It is time to evaluate these enhanced bioavailable fenretinide formulations in a clinical setting as drug combination regimens. Cancer is a heterogenous disease, both within the patient population and within a single patient. Cancer therapy will likely become combination therapy.
Fenretinide Drug Combination Studies Registered on ClinicalTrials.gov*
*Accessed September 20, 2022
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